text:
The two party system has its flaws, not the least of which is the tendency to polarize. During this time, during any time, if we are going to stand as a nation, North and South, right and left, self and other, we must recognize the need for the opposing point of view. We need to respect the fact that there is a source for the differences, and insist on a reasonable exchange. We cannot win over the “other side” if we threaten them. Name calling- nope. Reason. Tell me why you think that, and let me tell you why I think the way I do. Keep the calm in the storm. Value each other. There are no expendables. Democracy is the ends and the means, and includes all voices. Each of us must insist on all of us.
Category Archives: Uncategorized
In my undergraduate work from 1984 to 1988 at NMSU, I had the privilege of working for the PBS station there, KRWG, doing some video work and editing. I was neither here nor there about politics. I had worked with Jim Laukes, who had done a series of oral interviews, largely focusing on the relationship of the National Labs and NMSU.
In editing some of the “teasers” for the episodes, there was one with Major General Hugh Milton that I remember. There is a statue of General Milton outside of the Journalism building which also carried his name, when I went to school there. This was the Reagan era, and I predicted that General Milton would be all about military might. This was the Cold War, and I was young.
He said, “In a 100 years there has never been such change. Do we understand it? The answer is ‘no’.” In the course of the interview, General Milton put his arm out on the table. In talking about the Cold War build-up he continued…”Our country is hiding its greatest virtue under a bushel. The might of The United States is not in strength of its weapons, but in the promise of freedom”.
It was a moment when my prejudices were exposed, and proven wrong, and I was humbled when I realized it. I think of that now. The great virtue of the promise of freedom.
After all the millions spent on testing, as a state we are educationally and economically worse off than when we began to replace instruction with measurement. The best correlation to a test score remains socioeconomic status, a test score has no correlation to student success, and yet we perseverate knowing that there are significant variables that cannot be captured on a test. The premise of the reform was that having just three good teachers during the course of schooling is a boost to student outcomes, so we went to work evaluating teachers instead of improving their training. If we apply resources at the beginning of the pipeline, rather than the end, we can change things. Rather than pursue this until we are utterly spent, let’s go with what we know works.
- We know that the better educated teachers are, the better the outcomes for students, which is true even before a student begins school. If we improve requirements for teacher education, we improve student outcomes. (1,2)
- We know that if those teachers are paid well enough, they are more likely to stay, and we know that teacher experience increases student performance and attendance. (1, 2)
- We know that professional control of a classroom matters, that micromanagement by policy makers or site administrator is destructive to professional creativity and performance. (Citation pending)
We can end the soft bigotry and hypocrisy of moving resources further and further away from our diverse students while we expect them to test better. We can stop pouring millions out of our state on a course we have shown year after year to be a dead end.
It’s been a couple of years now, since my dad died, and I learned things from him, good and bad, as is done by all people everywhere in all relations- but he would say, in either case, its a “learning experience”, which would turn even the bad into something useful. That’s exactly the kind of platitude that would drive me crazy, but now resonates with me as a mantra in my role as a teacher, parent, spouse, and yet the offspring of someone in this place.
Mom was talking last night with one of my colleagues who just recently completed her PhD, about how she helped dad by typing his many hundreds of pages dissertation. It’s a story like many that I’ve heard many times, which becomes more valuable with each telling, stories like a favorite tune that plays on the last radio station that will play it, that I know I am inexorably getting farther and farther away from.
Today I remembered when one of my father’s professors from Northwestern visited us at my folks’ place. He was into his 90’s, and had been the sole reason my father got his PhD in geology, dad had told me that it was this man’s passion for the subject that gave him his passion for his choice. It was amazing to me that this guy came to visit, so many years later.
I think of this in my own teaching, that beyond the curricula there is the passing of the desire to learn. The modern age of “learning to pass the test” forgets this, in fact betrays this. I think of this quote from Einstein: “It is a very grave mistake to think that the enjoyment of seeing and searching can be promoted by means of coercion and a sense of duty. To the contrary, I believe it would be possible to rob even a healthy beast of prey of its voraciousness, if it were possible, with the aid of a whip, to force the beast to devour continuously, even when not hungry.”.
The passion for living isn’t found in the filling of roles, but in the adventure of life, and the excitement of learning. Learning is not the passing of information, the connections that come together create something new, in each person who makes those discoveries. For me, teaching is about this: the free thinking of people who live in a free society. The passing of that flame is the joy of life, that each person holds infinite possibilities of limitless direction, their own direction, not the learning of skills to fill a spot that was left empty by the cog that wore out before them.
I would like to be as my dad was for me, for my own daughters and students, to encourage their questions as adventures to explore. Life has not been done. It is this, it is happening, and I hope to feel its pulse and pass that connection. A new year’s toast, then, to the dead, and then to drink from life in their honor.
What can we do? New Mexico is now circling the drain in education, according to this August 2nd Albuquerque Journal article titled “New survey ranks NM’s education system almost last in the nation”. Let’s first learn from what we have done, which education is all about. Six years ago, New Mexico education was ranked around 35th by some measures, which people will contest, but certainly not near 50th by any measures. There certainly is room for improvement as 35th, but what happened that we are now almost dead last? We collapsed our elected state education board to a single “education secretary” position, designated by the governor. This was to bring us swiftly into compliance with the federal law, remnants of the “No Child Left Behind” which evolved into “Race to the Top”, with packaged deals from publishers and test companies. Hannah Skandera, our Education Secretary, is the chairperson for the PARCC organization, whose test is the statewide tool.
The implementation of these reforms were rushed and feedback about their effects on the classroom was assumed to be whining from stationed individuals that needed turning. The reforms were put in knowing that there would be “collateral damage”- casualties in with the old guard in teaching, etc., that would be well worth the trade if we could just hold to the long view.
Six years later, with end-to-end years of hundreds of teaching vacancies, budget cuts, and sinking morale, Skandera reports that it is the educator’s attitude that is the actual problem, and it will take decades more to fix, according to the Journal article dated January 13, 2016, titled “Skandera blames NM education troubles on low expectations”.
More than pointing fingers, and saying to wait “decades”, we should go ahead with a plan to improve things NOW. Let’s stop spending millions of dollars on out-of-state student tests and textbooks, and teacher evaluation companies whose products clearly have not improved anything in our state. Many of those things are available RIGHT NOW for free online. Ask me how, I know how to do this. So do many of us. This is not military protocol, for us to “do as we are told”. It’s what the military fight for: our democracy. Hear our voice, and we can teach.
Monte Vista Elementary
Educators, help build: OpenSourceEd.org.
When you become a teacher, you know you aren’t going to end up in Forbes, and that’s okay. The trade you make is the gratification that at the end of the day you’ve done an honest day’s work, you’ve helped others, and are a part of the promise of a free society; the continued implicit promise by the state which sponsors you, that we are still working toward the starry-eyed ideals which you signed on to: that we still believe in liberty and justice for all, that no matter what situation you were born into, our society agrees to level the playing field for awhile, to allow any child access to know what others know, and a chance that with that knowledge a person may elevate their own status and condition. Public Education is the place where we yet try to suspend marketplace forces, and truly, for a time, attempt a foundation of liberty and justice for all, the cradle of our civilization, the hope of free people.
When you unleash the hounds of marketplace forces, you unleash again the forces of inequity, and people are held responsible for the circumstance into which they were born. Social strata are reinforced in this, and a caste-system is created with no holding out of hope for the ideals which we started out with. Teachers who once took up that yoke because they believed in what they were doing, like soldiers who find out their cause is not just, lose the benefit of the strength of belief in their cause, become mercenaries instead, and may work to contract, or if it is just another job solely for the purpose of making money, without ideals, then teachers may choose a job that makes more money.
There is a teacher shortage in America.
Instead of working toward improving the education and training of teachers, paying teachers more money, or improving infrastructure, the country is opting for simple minded solutions such as Teach For America, and other band-aids, which actually reduce the training and qualifications of teachers, as well as reducing the numbers of those who want to become teachers. See these articles about Georgia, Utah,Wisconsin, New Mexico, California, and really, the whole country. I was at a meeting last night where it was reported that some districts in Illinois are traveling to Europe to recruit teachers. They are now paying third parties to guarantee some of their own graduates go into teaching for a minimum of five years, rather than simply raise the salary of teachers directly.
Last week, while working on our OpenSourceEd.org development camp, a teacher told me that the definition of public schools in New York is that you now apply for a public school, the “good schools” get first dibs, and students who don’t make the cut, go to the schools which get “the leftovers”. We are no longer working toward our ideals, the great melting pot, the opportunity to rise. In these incarnations we are reinforcing socioeconomic disparity.
Sound the alarm. Lines have been crossed, public schools are shutting down. When charter schools, and private schools, coexist with properly funded, professionally staffed neighborhood schools, then all is well, but service is now denied to children because money and advocacy have been siphoned into exclusionary settings. With this we make a lesser promise to future generations. Remember your pledge, remember the ideals of liberty and justice for all. With all of the problems and drudgery that Public Education has, it still is hope to fulfill that pledge. Public Education is still worth fighting for.
Do you have lessons, tests, resources, and ideas that you would like to give away, and make sure they don’t get sold back to you? Do you think that knowledge is power and the distribution of it is democracy? Would you like to get professional development while developing your profession?
Come to the OpenSourceEd.Org development camp, Monday June 13 through Thursday the 16th from 9 am to 1 pm at Monte Vista Elementary’s Library! Come for all! Come for part! Drop off your ideas if you can’t stay! Come and change the profession if you can! Snacks will be provided! Bring a laptop if you can! It’s free! Exclamation mark!
Right now, I’m certain someone is working on one of those read aloud book-apps, like the Alice in Wondeland App, but instead of just reading what you need read, it eventually prompts you to read to it. The speech to text technology already exists, sort of, (my phone misunderstands me every time I try)…so somebody is working on a comparative software that will assess the accuracy of a persons reading capability, maybe even coach inflection and articulation. By the way, if you invent it after reading this, how about some recognition, maybe a Dr. Pepper or something.
So, taking that a bit further, I was thinking that soon such a device, perhaps an interactive video, (a la the old Hypercard wonder “Animal Pathfinders“, which, by the way, I can’t believe hasn’t been reincarnated on the web with full interactivity- and again, if you do this that is a second Dr. Pepper)- would read and “listen”, and asses reading skill, but also listen for social markers. For example, I often will read “Huckleberry Finn” (the kids version) to my class – not just because it is great, but because almost every year a student will divulge their own abusive situations to me when we are reading about Huck’s dad. I’m certain this saved the life of one of my students, who was moved to another state away from her abusive step-father and enabling mother. I imagine an interactive listener reporting, when it asks about if student relates to a particular character or happening with some frequency by the way of moving through a book, that when a student says “yes- I want to escape like Huck” – that it sends a message to the teacher, a marker that indicates an anamoly to be followed up on.
Should we do this? No, We shouldn’t. Further loss of human interaction as a child learns literature – the early experience will be deprived of the subtle implicit and explicit sharing of emotion and imprinting of value hierarchies and nuance. Non-scripted questions, or reactions that fall outside of programmed algorithms will create a void of interaction, essentially teaching sociopathy. It hearkens situations much like the rules for administering standardized tests now- where teacher is replaced with monitor, who must not help, but is a mute, insane pausarius. The supplemental tool of a “listening book” under the auspices of the teacher could be a useful tool, but some Koch brother clone will see it as a grand money making scheme to replace teachers with, sure as Walmart sucks.
Then I thought of a story, which I will tell you another time.
Those kept warm by the glow of synaptic fires
from behind dilated Pupils
know the worth of the light
walk in the face of the blasting wind
that comes in little pay, or politics,
or any of the social morays
and other eels of society
and strive anyway
to pass on the flame.
First of all, thank you for your service. There is no doubt sacrifice on your part to do what is right for the people you represent and toward that idea of a more perfect union.
It is for this purpose I ask you to change the structure of education in New Mexico. Over a decade ago, we replaced a State Board of Education because of the gridlock of representatives arguing over their constituents’ best interests, and who may have missed the broader view of education in New Mexico, for a streamlined “Secretary of Education,” whose implementation of policy has not yielded the promised results across the state. Graduation rates are down, test results are down, class sizes are bigger, higher education enrollment is down, teachers are leaving the state, so the state is creating waivers for teachers to teach other subjects, and many other people are leaving the state, too. Feedback about the negative effects of the implementation and policy have been met with threats to the democratically elected school boards rather than discourse, in Las Cruces, Deming, and in Albuquerque. There is no indication that the “Secretary of Education” approach has improved education in New Mexico. There is also a strong possibility that this model will represent constant political swing, as different governors are elected, rather than a more stable foundation of policy.
We need a revised democratically elected State School Board System, whose backgrounds are k-12 education, which represent different geographical areas of the state, which keeps in check the currently unchecked position of Secretary of Education, which has the power to advise, veto, repeal, and override the Secretary of Education.
Please consider legislation to improve the accountability in our government. Thank you,
Jeff Tuttle …

domain: politics


text:
Preston North End manager Simon Grayson says his players can hold their heads high following their fifth round FA Cup exit to Manchester United.
But, result aside, Grayson said that the players had done themselves proud.
Speaking to PNE Player, the gaffer had this to say: “We said to the players in the pre-match talk and leading up to the game that we wanted them to go out, work hard, and wake up in the morning having done yourselves justice.
“I think all of them will wake tomorrow and be tired physically and mentally but they can be proud of what they have done.
“They have carried out what we asked them to do, sometimes you get the breaks, sometimes you don’t get the breaks against the top teams, but we have done immense work to try and get the result tonight.
“Unfortunately we have not got the result but we have put on a performance and given a right good account of ourselves.”
You can watch the full interview with Simon Grayson on PNE Player now by clicking here.

domain: game


text:
Jenna Johnson Says Karamo Brown Would ‘Queer Eye’ The Cast Of ‘DWTS’
Before they could share with the world that they were going to be Dancing With the Stars partners, Johnson and Brown enjoyed some quality time in Maui getting to know each other–the calm before the storm.
“We weren’t allowed to announce who are partners were leading up to the premier but Karamo and I actually went to Maui together–not for fun, I wish–he was working out there and I got to tag along. We got to go to dinner every night together, I’d go with him and his fianceé, and we just had the best time and I really got to know him in those few days that we had,” Johnson told Showbiz Cheat Sheet.
“It was off-camera, we were just by ourselves… I really loved those moments before all of the chaos was about to go down. That’s one of my favorite memories, sharing that trip together,” she added.
Why Jenna Johnson and Karamo Brown worked so well together
When they finally began rehearsing, Johnson says she quickly realized how good of a pair she and Brown made.
“What you see with Karamo is what you get. He’s so enthusiastic and he’s really welcoming and inviting and I think he genuinely cares about getting to know each person he comes in contact with. So I immediately felt that with him when we first met. I think that our personalities meshed really well together. We don’t take things too seriously, we love to laugh together, and I think it created a really spectacular friendship. I think people could read the energy on and off-air,” she said.
You can take Karamo Brown off of the ‘Queer Eye’ set but you can’t take the ‘Queer Eye’ out of Karamo Brown
Queer Eye fans are probably pleased to learn that Brown is the same Karamo we see on the Netflix makeover show even when he’s not filming. Johnson says, in true Karamo fashion, that her partner helped her realize she could be a little better at accepting compliments.
“He helped me with the struggle of receiving compliments from other people, especially loved ones. I never had been told that I had a hard time doing that but it’s really true. That was a really great moment for me to reflect and be like ‘Oh wow.’ I think just hearing it from him and just trusting that he knows what he’s doing in that field, I accepted it and was willing to be like ‘Wow, I do need to work on this.’ So that was a little Karamo moment that I received,” she said.
But Brown didn’t work his Queer Eye magic on just Johnson. The professional dancer says her partner would “Karamo a lot of people.”
“I also watched him Karamo a lot of people, especially on the cast. It was great to see him do that because I felt like I was watching an episode of ‘Qeer Eye,’ just a live version of it,” she shared.
Jenna is proud of the work she and Karamo put in
Unfortunately, Brown and Johnson were eliminated from Dancing With The Stars last night. Johnson says she wouldn’t have done anything differently if she could go back in time. In fact, Johnson says that both she and Karamo are pretty happy today.
“I feel actually really happy today,” she said. “Karamo and I are in great spirits. I think we had a fantastic night last night. So I’m really just happy and content.”

domain: celebrity


text:
Francistown Senior Secondary School, is located on the
out skirts of Francistown city, off the Maun road, which is a get way
into the famous Okavango Swamps. Francistowncity is the second
largest city in Botswana. It is about 440 km. from the administrative
and commercial capital of Botswana. Botswana is located in southern
Africa sharing, borders with South Africa in the south,
Nambia in the west, Zimbabwe in the East and Zambia in the North.

domain: geography


text:
Supplies: Stamp Sets: All Holidays, Punch Potpourri; Cardstock: Ivory Naturals, Marina Mist, Paisley Prints DSP; Accessories: 3/8" Taffeta Ribbon, Corner Rounder Punch, Boho Blossoms Punch, Dazzling Diamonds Glitter
First I would like to say a big Happy Mother's Day to my Mom and to all Mother's out there!! Here is the card I made for my Mom this year. My Mom's favorite color is blue so that is what started my process in making her card. This is the Paisley Prints DSP that was in the April promotion and will not be back until July when the new Catalog is out. The greeting is part of the All Holidays stamp set, and the flowers come from the hostess set Punch Potpourri. The ribbon is 3/8" Marina Mist Taffeta Ribbon, I also used dazzling diamond glitter on the flowers and on swirls by the greeting!
I am happy with how this card turned out, it simple yet elegant! I am sure my Mom will love it.
To Shop Anytime go to my Online Store!
Thanks for Stopping and Happy Stampin'!

domain: design


text:
Dive into luxury staying at Sapphire. The villa offers an extensive range of facilities that include a comfortable and chic living room, a superb modern and fully equipped kitchen and dining room, 3 luxurious marble bathrooms and 3 stunning bedrooms.DISCOVER
The perfect location of Sapphire villa lets you enjoy the fascinating view that opens up to you across entire Souda Bay. You will be delighted by the seamless modern architecture of the villa with some traditional elements specific to Greek islands, the privacy of Sapphire and its luxurious swimming pool. (Τhe pool can be heated at an extra price of 50 euros (€) per day for minimum 3 days usage.)DISCOVER
Enjoy a variety of SPA therapies in your own bedroom.
Relaxing massage by an experienced professional upon your demand.
Free yourself from the chores of cooking and enjoy the finest gastronomy of the region.
Just choose a destination and enjoy the incredible landscapes of island Crete.
Rent a vehicle and explore Crete at your own pace.
Discover different sides of Crete and learn about the local way of living.
Taste the finest local wines with delicious pairings and learn about the particularities of winemaking in Chania region.
Treat yourself to the full at your own home.
Leave your children to a highly qualified babysitter over different educational and entertainment activities.
Enjoy our heated pool in all seasons

domain: travel


text:
Krystal Richmond Photography is a seasoned photographer located in Kankakee, Illinois servicing all of the Chicagoland &...Read more Quad Cities area as well as traveling the Midwest. This professional shooter captures beautiful portraits and genuine candids throughout a couple’s big day. Whether you’re having...... (Wedding Photographers)
MDL Events began in 2008 helping couples celebrate their magical day by providing music & entertainment all across Iowa....Read more With years of wedding experience, this eventually led to expanding our services to be able to help couples capture those memories with the addition of photography and videography....... (Wedding Photographers Waukee)
Hi, I'm Chelsea! I'm a documentary-style photographer specializing in weddings, intimate ceremonies, and elopements.
I...Read more believe my purpose is to tell the story of the day as it naturally unfolds, not to write it, necessarily :) I value people over things, as well as moments over aesthetics.
I am a...... (Wedding Photographers Janesville)
Jamie Orr Photography is a freelance wedding photographer based in Cedar Falls, Iowa. While located in Cedar Falls,...Read more Jamie Orr Photography can serve all of Northeast Iowa and its surrounding states. Owned and operated by Jamie, she boasts years of experience and believes nothing is more important...... (Wedding Photographers Cedar Falls)
TYS Photo | Video is a wedding videography and photography business located in Rock Island, Illinois. TYS Photo | Video...Read more specializes in high-quality videos and photos that portray a cinematic and timeless. We love the way movies make us feel and look at life. Our wedding videos are meant to evoke the...... (Wedding Photographers Rock Island)
ORGANIC + ARTISTIC CANDIDS
Hi! I’m Scott, and I’m the photographer behind Magenta Wedding Photography....Read more Welcome!
Photography is about the moments of the connection and telling that story by being organized, thoughtful, and creative.
I love what I do, and share my experiences with brides and grooms. I...... (Wedding Photographers Davenport)
Three Sisters Photography is a family-owned business based out of Eagle Grove, Iowa, but we love to travel! We are...Read more down-to-Earth, fun-loving, and easy-going. Our guarantee to you is an unforgettable experience where you can relax and trust that your special moments are in good hands.
Three Sisters...... (Wedding Photographers Eagle Grove)
Cukini Studio @ Studio Reserved offers beautiful contemporary wedding photography for your special day. Based in an 100...Read more years old church building in downtown Cedar Rapids, Iowa, the Studio has experience working in various regional areas including Cedar Rapids, Marion, Iowa City, Coralville,...... (Wedding Photographers Cedar Rapids)
Jane Wiggins Photography creates stunning photojournalistic images that will allow you to cherish the special memories...Read more of your wedding day forever. This photographer, located in the Cedar Rapids, Iowa, area, captures all of your intimate moments of romance in extraordinary ways. Jane Wiggins...... (Wedding Photographers Waterloo)
We specialize in that extra touch. Anyone can photograph your wedding. We will give you moments in time capturing the...Read more event in a special way. We are a husband and wife photography team that specializes in providing the personal touch to your wedding images. Do you have a style you want for your...... (Wedding Photographers Monticello)
George Street offers unparalleled photojournalistic photographic talent and creativity, personalized customer service,...Read more and prices for any wedding budget. Our couples receive a complete set of all digital negatives taken on their wedding day! Our experienced staff of photographers serve to capture...... (Wedding Photographers)
COLORADO + IOWA + DESTINATION
REQUEST AN ELECTRONIC BROCHURE: https://www.weddingsbycarue.com/contact/
Our fun loving,...Read more award winning wedding team makes it happen. We’re passionate storytellers. We believe that natural, REAL moments with REAL emotion are the moments you’ll want to remember the...... (Wedding Photographers)
If you're planning your Midwest or destination wedding, you've come to the right place, Geno Photography, based in Iowa...Read more City, serves Iowa City, Cedar Rapids, Des Moines, and beyond. If you've come to find out more about what Geno Photography has to offer, you are probably super-excited about your...... (Wedding Photographers Iowa City)
Quad Cities Wedding Photography Specialists...We Capture Moments! Our style of wedding photography is a blend of...Read more storytelling/photojournalism, artistic/creative, relaxed traditional portraits with some illustrative and fashion imagery. Our approach to your day will make your wedding photography a...... (Wedding Photographers Moline)
Alexander Michl Photography is an intimate photographer for a couple’s wedding in Iowa. This photographer captures the...Read more personal and emotional moments between couples on their wedding day. Every shared smile and tear is recorded. Photographer Alexander Michl captures weddings throughout the Des...... (Wedding Photographers Clive)
Mary Steere Photography, a photography company in Mason City, Iowa, provides services throughout Iowa and the entire...Read more country. Mary Steere, the owner and lead photographer, uses either traditional wedding images or candid images in documenting the couples’ event.Services Offered Mary Steere...... (Wedding Photographers Greene)
Moses de los Santos Photography is a wedding photography service based out of Amana, Iowa. This professional photography...Read more studio specializes in capturing the uniqueness of every wedding day. Moses has over eight years of experience in capturing special moments, including all of the laughter, tears,...... (Wedding Photographers)
Based in West Des Moines, Iowa, Extreme Photo is a photography company that specializes in portrait, wedding, glamour,...Read more and boudoir photography. The photographer shoots regularly in Des Moines, Urbandale, Clive, Waukee, Johnston, Ankeny, Winterset, Ames, and other areas around central Iowa. With full...... (Wedding Photographers West Des Moines)
Wedding Day Package... Coverage before the Ceremony and into the Dance, Enhanced Digital Images with Print Permissions,...Read more Online Galleries to Share with Family and Friends, Two Professional Photographers, Free Engagement Session, and Free Iowa Travel... $1895... (Wedding Photographers Urbandale)
Amelia Renee Photography is a professional wedding photography company based in Des Moines, Iowa. Owner and...Read more photographer, Amelia Renee specializes in in portrait, wedding, engagement, senior, and family photography. Amelia primarily provides services in the local areas of Des Moines, Ames, and Cedar...... (Wedding Photographers Des Moines)
Finding a wedding photographer is not only about choosing a pro who takes great pictures. Personality plays a big role in selecting a wedding photographer—you’re going to be spending a lot of time with your photographer...Read more on your big day! Browse these wedding photographers to see examples of their work and read reviews from past clients.

domain: artistic


text:
Positron emission tomography (PET) combines radioactive tracers and mathematical models to determine the kinetics of bioactive tracers involved in certain physiological phenomena. With this method, the measurement of a certain radiotracer concentration in the nervous tissue is represented through a 3-dimensional image, which ultimately represents the anatomical distribution of the biological process under evaluation. Positron emission tomography has allowed researchers to quantify the availability of several receptors in vivo. The receptors studied include serotonergic, dopaminergic, and opioid, among various others, which can be evaluated either in baseline conditions (eg, at rest) or during specific challenges, such as cognitive tasks, experimental pain, or even the administration of a placebo.39,57,70–75 Moreover, with this method, it has been possible to study the dynamic functioning of some of the major endogenous pain modulatory systems (eg, dopaminergic and opioidergic) and their interactions in different neuropsychological disorders, including depression,32 addiction,47 and chronic pain.25 For instance, an early PET study conducted in patients with chronic pain revealed that fibromyalgia, a disease with unknown pathophysiology and challenging clinical management, is associated with a decreased availability of mu-opioid receptors, the main target of opiate analgesics, in several pain-related regions including the amygdala, nucleus accumbens (NAc), and cingulate cortex.25 Interestingly, a comparable pattern of mu-opioid receptor activation had been demonstrated earlier in a group of healthy volunteers subjected to experimental sustained pain.73 Those initial PET studies, which used a radioligand that selectively binds mu-opioid receptors, provided novel information at that time regarding the endogenous regulation of the pain experience by the opioid system. The changes observed in brain areas related not only to the sensory but also to the emotional and cognitive aspects of pain and also corroborated the concept of pain as a multidimensional experience, introduced many years before.41 Those findings were further expanded to other chronic pain conditions, such as trigeminal neuropathic pain19 and migraine headache.16,45 Although those studies used the selective mu-opioid receptor radioligand [11C] carfentanil, similar findings have been obtained using the nontype selective opioid receptor radiotracer [11C] diprenorphine, which has also been largely used to study the role of the whole opioid system in chronic pain syndromes. For instance, increased availability of opioid receptors in the frontal, temporal, and cingulate cortices was associated with decreases in the inflammatory pain of patients with rheumatoid arthritis in a past study.28 Another study with [11C] diprenorphine described the presence of reduced opioid receptor availability in both cerebral hemispheres of patients diagnosed with peripheral neuropathic pain.68 Of note, in patients with neuropathic pain, the decreased availability of opioid receptors was predominantly located in the hemisphere contralateral to the reported pain.37 Such findings could indicate a higher release of endogenous opioid peptides (eg, enkephalins) driven by pain, resulting in higher occupancy and lower availability of opioid receptors (Fig. 1), or alternatively, a downregulation or even loss of opioidergic neurons, with both scenarios associated with a prolonged pain experience. This specific question has been recently addressed in an experimental model study62 and will be discussed later in this article. The results obtained in PET studies, from a clinical perspective, might help to explain the lack of efficacy of opioid analgesics, a class of drugs that has been applied in the treatment of cancer and postsurgical pain13,27 but usually fails to provide adequate relief in other pain syndromes, including fibromyalgia and chronic neuropathic pain.23 Based on these findings, it has been hypothesized that each chronic pain condition may be related to specific changes in the opioidergic system. Therefore, it is important to consider the effects of selected genetic polymorphisms on individual differences in the opioid system response to pain and placebo treatments. These differences have been investigated through PET and will be discussed in this article.
2. Opioid system activity related to pain
Pain has been described as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage,”43 a definition that derives from the concept the multidimensionality of pain. This fundamental concept, initially introduced in the 1960s42 is still extremely useful to understand the complexity of the pain experience, which goes far beyond nociception (sensory dimension), with its important affective (motivational) and cognitive (evaluative) dimensions. However, with the enhancement of neuroimaging techniques, it has been possible to corroborate and consolidate this model. Magnetic resonance imaging (MRI) studies have provided valuable information regarding functional changes (eg, altered connectivity, metabolism, and hemodynamics) as well as structural changes (cortical thickening, thinning, or altered volume) that occur in the brain driven by pain. In addition, some previous PET studies showed increases in the regional cerebral blood flow related to noxious thermal stimuli of different intensities when compared with innocuous thermal stimulation. The results of such studies suggest that changes in the regional cerebral blood flow associated with noxious but not to non-noxious thermal stimulation could represent neuronal changes associated with nociceptive processing driven by pain.11 Other PET studies have confirmed the presence of changes in cerebral blood flow induced by noxious stimuli and have even revealed the brain regions that contribute to each aspect of the pain experience. For instance, 1 PET study that evaluated the effects of noxious heat stimulation on the regional cerebral blood flow confirmed the major role of the thalamus in the processing of pain intensity. However, according to the results of that study, pain unpleasantness may be more associated with the activity of the posterior part of the anterior cingulate cortex (ACC).63 Nonetheless, these findings added limited, although extremely relevant, data regarding the activity of specific neurotransmitters and modulatory systems related to pain processing and modulation. With this respect, PET studies that applied selective or nonselective radiotracers to investigate the functioning of particular modulatory systems related to noxious stimulation have contributed significantly to the study of pain, providing important insights into the molecular mechanisms underlying the pain experience as well as the placebo analgesia and the nocebo effect.
In one the first PET studies that used the selective mu-opioid receptor radiotracer [11C] carfentanil, Bencherif et al. demonstrated a decreased mu-opioid receptor availability in the contralateral thalamus related to a noxious stimulus (eg, capsaicin, applied to the dorsal aspect of the hand of healthy volunteers). Interestingly, this decrease in mu-opioid receptor availability in the thalamus directly correlated with the subjective pain ratings. These results suggested a release of endogenous opioids driven by acute pain. They were also important to demonstrate, in vivo, the involvement of the mu-opioid neurotransmission in the supraspinal regulation of pain perception.8 In a later study, Zubieta et al.72 investigated the activity of mu-opioid receptor-mediated neurotransmission in vivo during a sustained pain challenge, obtained through a controlled injection of 5% hypertonic saline or a placebo into the masseter muscle of healthy volunteers. The results demonstrated the activation of the mu-opioid system associated with an ongoing pain experience. Such activation was represented by a lower availability of mu-opioid receptors during the pain challenge when compared with the placebo phase. Strikingly, those changes were found in a wide variety of pain-related brain structures, such as the amygdala, thalamus, hypothalamus, insula, prefrontal cortex (PFC), and dorsal ACC. These findings served as a basis to further PET studies, and consequent investigation ultimately confirmed the same pattern of mu-opioid activation in patients with different pain syndromes.16,19,25,45 Interestingly, a recent PET/MRI study demonstrated that the mu-opioid system is not only involved in self-experienced pain but also regulates the neural mechanisms that trigger the unpleasant sensation of seeing others in pain, namely vicarious pain (an essential component of the human behavior). More precisely, a negative correlation between hemodynamic changes (eg, blood oxygen level dependent [BOLD] signal) and mu-opioid receptor availability was detected in the insula (anterior and posterior), thalamus, primary motor cortex (M1), primary and secondary somatosensory cortex (S2), paracentral lobule, supplementary motor area, and PFC. Given these findings, these brain regions appear to process the negative features of pain as well as play a role in the sensory-discriminative mirroring of others' pain. On the other hand, the availability of mu-opioid receptors in the orbitofrontal cortex (OFC) was positively correlated to its BOLD activation induced by vicarious pain, which could possibly be linked to a role of this brain region in socioemotional functions and mentalizing. Importantly, the involvement of dopamine D2 receptors could not be demonstrated in that study.29
Zubieta et al.72 also demonstrated a substantial interindividual variability in both receptor availability and in the activation of the mu-opioid system in healthy controls experiencing same level of pain intensity. In these, and subsequent studies, the pain intensity was controlled (moderate pain was kept constant at around 40 in the visual analogue scale throughout the whole period of the experiment) (Fig. 2). These results added important data, which, at least in part, explains the very large variability in pain experience across individuals. This variability embodies a fundamental consideration when deciding the most adequate therapeutic approach to treat each patient with chronic pain. Interindividual variability in mu-opioid activation was also implicated in the vicarious pain study and very likely accounts for the differences in the reactions of seeing others in pain, which were clearly detected among individuals.29 Furthermore, the variability in individual responses to pain, as well as in the functioning of the endogenous antinociceptive mechanisms, has also been attributed to genetic factors. This information is paramount from the perspective of clinical pain management, particularly when evaluating individual susceptibilities to chronic pain development, the prediction of treatment outcomes, and the choice of the most appropriate therapies to treat each subject (individualized treatments). Indeed, genetic variants may not only interfere in the protein coded by a gene but also in the physiological activity of several neural systems, including the opioidergic system. Thus, the role of genetic polymorphisms on the antinociceptive activity of the opioid system has also been examined through PET.
Early evidence regarding the genetic component of pain processing comes from a PET study that used a selective opioid mu-opioid receptor radiotracer to investigate the effects of the abundant polymorphism of the catechol-O-methyltransferase (COMT) gene, which codes the replacement of valine (val) by methionine (met) at the codon 158 (val158met), on the mu-opioid activation induced by a sustained pain challenge74 in healthy subjects. Since COMT is one of the enzymes that metabolizes catecholamines, it is involved in the regulation of noradrenergic and dopaminergic systems and may indirectly affect opioid neurotransmission. This study reported that the mu-opioid activation induced by the sustained pain challenge was significant lower in met/met healthy subjects, which have a lower COMT activity, when compared with val/met subjects, which present an intermediate function of the same enzyme. Those differences were found in the striatopallidal pathway nuclei and amygdala74 (Fig. 3). These COMT polymorphisms (val158met) were also accompanied by higher sensory and affective ratings of pain in healthy subjects. A more recent study has confirmed that in chronic temporomandibular disorder pain, COMT polymorphisms (met/met-met/val) have induced higher pain sensitivity, but with changes in mu-opioid activity in the limbic system. Hence, further studies should be performed to better understand the effect of COMT polymorphism and mu-opioid activity in multiple pain conditions and disorders.44
Other polymorphisms affecting the activity of the mu-opioid system have also been studied. For instance, the A118G polymorphism of the mu-opioid receptor is a single nucleotide polymorphism characterized by the substitution of adenine (A) to guanine (G) at codon 118 (A118G) in the human OPRM1. This is related to a lower expression of the OPRM1 gene.69 Hence, it interferes with pain sensitivity as well as the outcomes of pain treatments, with important effects on the modulatory activity of the opioid system. This polymorphism has been recently investigated in clinical pain conditions.66 For example, patients with primary dysmenorrhea were evaluated through functional MRI (fMRI). The results showed that the individuals who carried the G allele had functional hypoconnectivity between the ACC and periaqueductal gray matter (PAG) when compared with AA homozygotes, which also correlated with the spontaneous menstrual pain. Patients with primary dysmenorrhea carrying the G allele exhibited no correlation between PAG-seeded FC and their menstrual pain. These findings indicated a decreased opioid modulation of pain in G allele carriers. The results of that study also brought important insights into the mechanisms of pain in dysmenorrhea, and such data help to explain the great individual variability in the pain experience reported by those patients. A later study reported that other genetic variations in the mu-opioidergic system, more specifically, the presence of the T-allele of the rs563649 polymorphism on the mu-opioid receptor, may influence the prediction of the development of pain complaints at the ages of 16 to 17 years, from behavioral and functional indicators (eg, reward feedback–related response in the ventral striatum and PAG) obtained at earlier ages (14–15 years).46
A negative correlation has also been demonstrated between the sensory features of pain, evaluated through the sensory score of the McGill Pain Questionnaire (MPQ) and the degree of mu-opioid activation in the thalamus, NAc, and amygdala using the model of experimentally induced sustained pain previously described.73 The presence of the same correlation in the PAG, although not reaching the statistical level of significance, assigns an antinociceptive function to the amygdala, possibly through its connections to the PAG, a region with a dense concentration of mu-opioid receptors and an essential element of the descending pain modulatory system.40 The correlation between the NAc mu-opioid activation, a key component of the reward circuitry21 with the sensory pain ratings found in the same study, indicates the contribution of this structure to the antinociceptive effects produced by mu-opioid receptor activation. In addition, significant negative correlations were found between MPQ affective scores and mu-opioid receptor activation in the NAc as well as in the ACC and thalamus. The changes in thalamic mu-opioid activity are also relevant. A recent fMRI-PET study demonstrated a colocalization of changes in opioid receptor availability measured with [11C] diprenorphine and the hemodynamic changes in the brain obtained through changes in the BOLD signal within the thalamus, mediated by noxious pressure stimulus in healthy subjects.67 These findings were interpreted as a possible inhibition of thalamic neurons by a release of endogenous opioids induced by the painful stimulus.
Taken together, these results suggest that the antinociceptive effects of mu-opioid receptor activation by endogenous opioids are not only important to reduce the sensory aspects of pain but also to relieve its affective features. Such results also opened possibilities to investigate the relationship between mu-opioid receptors and their relationships with other systems important to pain and inflammation, which was explored in a following study.
Using the model of sustained pain previously described, a PET study revealed a significant negative correlation between the baseline plasma levels of the proinflammatory cytokine interleukin 1β (IL-1β) and the availability of mu-opioid receptors in the amygdala. In that study, subjects with higher levels of IL-1β showed lower mu-opioid receptor availability in the amygdala along with higher pain sensitivity.52 On the other hand, during a pain challenge (sustained pain applied to the masseter muscle), the activation of mu-opioid receptors was positively correlated with the plasma levels of Il-1ra (antinociceptive cytokine), but not with the plasma levels of IL-1β in the dorsomedial NAc. Nevertheless, the analgesic effects produced by the mu-opioid system activation during the pain challenge were counterbalanced by changes in IL-1β. For instance, subjects that displayed higher pain-induced release of IL-1β experienced less opioid-induced analgesia. The effects of IL-1β in the functioning of the opioidergic system have also been demonstrated in in vitro and in animal model studies. For instance, in a past study, IL-1β promoted an increase in the expression of proenkephalin and opioid receptors mRNA in primary astrocyte-enriched cultures.54 Furthermore, the release of IL-1β in the peripheral ganglia has been proposed as a possible mechanism to the attenuation of the analgesic effects related to morphine, a process that possibly involves the activation of satellite glial cells in the peripheral ganglia.9 In fact, bidirectional interactions between peripheral inflammation and central mechanisms as well as their contributions to the development of pathological conditions had been largely reported.4 Corroborating this concept, changes in the functioning of the opioid system have been found in patients with inflammatory pain.28 In addition to mechanistic studies, the contribution of the opioid system to pain has been extensively investigated through PET in cohorts of patients with episodic/chronic pain, and the role of mu-opioid activation in the pathophysiological mechanisms of different painful syndromes has just started to be unveiled.
3. Changes in the opioid system in painful syndromes and chronic pain
The results of MRI studies indicate that chronic pain is associated with structural changes in the central nervous system. Such changes include altered cortical thickness, eg, cortical thickening or cortical thinning, previously demonstrated in patients with migraine15,24 or changes in the cortical volume, eg, decrease cortical volume found in a cohort of patients with back pain.5 More importantly, those changes have been proven to affect multiple cortical structures involved not only in pain perception but also in the modulation of nociceptive stimuli. In addition, fMRI studies suggest the occurrence of colocalized functional and structural changes in the brain of patients with chronic pain.14 Nevertheless, beyond the presence of structural and metabolic changes in the brain induced by a persistent pain experience, PET studies have brought insights into the molecular neuromechanisms underlying the maladaptive neuroplasticity related to chronic pain. The use of PET in pain research has also helped researchers understand the individual viability related to pain, as well as long-lasting resistance to treatment, including to opioids found in refractory patients. Recent studies with (PET) using nonselective (eg, [11C] diprenorphine) radiotracers or [11C] carfentanil, a selective mu-opioid receptor radiotracer, have shown reduced mu-opioid receptor availability in some chronic pain disorders, including rheumatoid arthritis,28 neuropathic pain,37 and fibromyalgia.25
The first evidence of changes in the opioid system in patients with chronic pain dates back to the 1990s. A preliminary PET study performed in 4 patients with rheumatoid arthritis and using [11C] diprenorphine showed increased binding related to pain relief in several brain regions. However, more significant changes were reported in the temporal, frontal, and cingulate cortices.28 Similar results were obtained in a sample of 5 patients with central poststroke pain. Those patients presented lower opioid receptor availability in several pain-related brain structures, such as the thalamus, anterior and posterior cingulate cortex, midbrain, insula, PFC, S2, and parietal cortex, when compared with a control group of healthy subjects.68 Although still preliminary, those studies evidenced the presence of an altered opioid neurotransmission in chronic pain and highly suggested that a decreased availability of opioid receptors could be a common finding in subjects with chronic pain. In another PET study conducted in patients with arthritis (osteoarthritis, n = 15 and rheumatoid arthritis, n = 2) using [11C] diprenorphine, higher chronic pain levels were associated with increased availability of opioid receptors in the insula, PAG, basal ganglia, NAc, and subcallosal area in the group of patients, which could suggest upregulation of opioid receptor sites in patients with chronic pain who present higher levels of pain.10 The availability of opioid receptors in the caudate nucleus was also positively correlated to thermal pain thresholds in both patients and healthy subjects, supporting the role of the upregulation of opioid receptors within the striatum as an adaptive response to inhibit pain. Finally, the same study showed reduced levels of opioid receptor availability in the caudate nucleus of patients with chronic pain compared with controls, supporting the findings of the other studies. Nevertheless, a common limitation of those studies was the use of a nonselective radiotracer, which did not permit the identification of the specific opioid receptor affected by chronic pain.
In another work, Harris et al.25 used the selective mu-opioid receptor radioligand [11C] carfentanil to study the functioning of the mu-opioid system in fibromyalgia syndrome, a disease with unclear etiology and pathophysiology. The results indicated a reduced availability of mu-opioid receptors in the amygdala, NAc, and dorsal ACC of 17 patients with fibromyalgia when compared age- and sex-matched healthy controls. When analyzing the group of patients with fibromyalgia separately, the availability of mu-opioid receptors in the striatum and cingulate cortex was negatively correlated with the relative amount of affective pain, defined by the affective/sensory scores of the MPQ. Furthermore, the availability of mu-opioid receptors in the NAc was negatively correlated to the affective pain ratings. When expanding the findings obtained with fibromyalgia to other chronic pain diseases, reduced availability of mu-opioid receptors in the NAc was also found in a cohort of patients with trigeminal neuropathic pain.19 Those changes were also correlated with the clinical pain symptoms. Nonetheless, in the cohort of patients with trigeminal neuropathic pain, the availability of mu-opioid receptors in the NAc was negatively associated with the sensory and total pain ratings of the MPQ. The NAc is the main structure in the ventral striatum. Although very small, this brain region plays a crucial role in the reward circuitry and modulation of the nociceptive information. It receives afferent nociceptive inputs through connections with the amygdala, thalamus, cingulate cortex, and parabrachial nucleus. Moreover, the axis formed by the PAG, rostralventromedial medulla, and NAc exerts a crucial role in the descending pain modulatory system.40 The analgesic effects of several analgesic drugs, including opioids, highly depend on the proper functioning of those structures.2 Remarkably, changes in the BOLD signal of the NAc has been related to the onset (aversive) and offset (reward) of painful heat stimuli.7 However, even more important seems to be the changes in activity of the NAc in response to the offset phase of painful heat stimuli, which permitted the differentiation between patients with chronic low back pain and healthy subjects in a previous study.6
A PET/fMRI study performed in patients with fibromyalgia revealed a positive relationship between pain-evoked neural activity and mu-opioid receptor availability in the rostral ACC (rACC) and in the dorsolateral PFC (DLPFC). On the other hand, fMRI BOLD signals in several brain regions such as the medial frontal gyrus, posterior cingulate cortex, and ACC were negatively correlated with the affective/sensory pain ratio. Furthermore, higher mu-opioid receptor availability was negatively correlated with the affective/sensory pain ratio in the medial frontal gyrus, posterior cingulate cortex, ACC, and precentral gyrus.56 Based on such findings, the authors hypothesized that in patients with fibromyalgia, tonic higher levels of endogenous opioids would promote a lower affinity or a downregulation of mu-opioid receptors on GABAergic interneurons of brain regions involved in nociception. Hence, an inhibition of GABAergic interneurons related to a phasic release of endogenous opioid triggered by noxious stimulation, an important mechanism for the descending pain modulation, could be altered in fibromyalgia. More specifically, although in healthy individuals, opioid release results in the inhibition of GABAergic interneurons that tonically inhibit the neurons located in several brain regions such as the PAG, PFC, and ACC, thus causing disinhibition and excitation of antinocicpetive neurons, in patients with fibromyalgia, such phasic endogenous opioids release in response to nociceptive stimuli fails in producing adequate inhibition of GABAergic interneurons and a faulty antinociceptive mechanism occurs.56
The activity of mu-opioid receptors has also been studied in patients with episodic migraine during both its ictal (painful) and interictal (pain-free) phases. Increased activity of mu-opioid receptors in the PFC was reported during the ictal spontaneous migraine phase compared with interictal periods.16 Indeed, PFC activation had been previously shown in both triggered and spontaneous migraine headache attacks.1,18 Moreover, it seems that an increased mu-opioid activity in the PFC enhances the connectivity with the PAG, which is important to produce analgesia.65 In addition, the mu-opioid activity during the ictal and interictal phases of patients with migraine was positively correlated, corroborating the interindividual variability in the mu-opioid system largely reported and already discussed in this article.73 In a following PET study also performed in patients with episodic migraine, the activity of the mu-opioid neurotransmission in the red nucleus and PAG was positively correlated to the development thermal allodynia in an experimental paradigm using a heat stimulus applied to the ophthalmic (V1) region of the trigeminal nerve.45 The results of that study substantiate the concept of a dysfunctional response of midbrain structures to the nociceptive inputs received from activated afferent trigeminal projections as a mechanism of migraine headaches.30,61 Conversely, a recent PET study did not find differences in the availability of opioid receptors when comparing patients with episodic migraine and healthy subjects.34 However, the lower sensibility of diprenorphine,53 used to evaluate the functioning of the opioidergic system in that study along with the comparison at baseline conditions (eg, patients with migraine were scanned within their interictal phase), might explain their distinct results when compared with the previous studies.16,45
As previously mentioned, the findings of these studies could indicate a higher release of endogenous opioids related to pain or downregulation of opioid receptors, particularly mu-opioid receptors, or even both. Those hypotheses have only been recently tested by a PET study performed in an experimental animal model of neuropathic pain.62 The authors scanned Sprague-Dawley rats with [18F] FDPN, a compound analog of diphrenorphine. Animals were scanned 3 months after the spared nerve injury or sham surgery was performed. Animals that underwent the spared nerve injury exhibited lower availability of opioid receptors in the motor cortex and basal ganglia when compared with sham. Although a baseline scan was not performed, the observed changes were attributed to the presence of neuropathic pain, since all animals were exposed to the same experimental conditions. More importantly, the same study found a decreased expression of mu-opioid receptors in the basal ganglia and insula of the animals that developed a peripheral neuropathy, which was not followed by changes in enkephalin or in the neuronal marker NeuN, as demonstrated by immunohistochemistry. Considering those findings, the decreased availability of opioid receptors observed in the brain of patients with chronic pain might be interpreted as variations in the expression of opioid receptors triggered by pain rather than loss of opioidergic neurons (no changes in NeuN-immunoreactivity cell count between nerve-injured and control rats) or higher release of endogenous opioids (no difference in enkephalin immunoreactivity between nerve-injured and control rats).35 Nevertheless, the lack of a longitudinal evaluation (eg, preneuropathic and postneuropathic pain) is an important limitation that should be addressed in future studies. Moreover, to which extent those findings can be translated to other (non-neuropathic) chronic pain disorders, as well as to humans, are important aspects that must considered when analyzing such results. The use of selective radiotracers by future studies will also be important confirm the specific opioid receptor affected in this whole process. In addition, another important feature that has been scarcely explored and should be investigated in depth by future studies is the difference in opioid activation between somatic and visceral pain. For instance, at least 1 study reported that in contrast to somatic pain, sustained visceral pain is not related to an increased release of mu-opioid receptors, despite similar intensities, thus highly suggesting that endogenous opioids could play distinct roles in each type of pain (eg, somatic or visceral pain).36
4. Placebo-nocebo and the opioid system: an overview of the evidence obtained from positron emission tomography studies
The opioid system has been widely associated with the development of placebo effects since the discovery that that the placebo effect can be prevented by the administration of naloxone, an opioid receptor antagonist.33 Further studies demonstrated the central pathways involved in the placebo effect. This includes cortical areas, such as the ACC and DLPFC, the descending modulatory system components (eg, PAG and rostroventromedial medulla), as well as the dorsal horn of the spinal cord.22,51,64 In addition, the neurobiology of placebo and nocebo effects has been investigated through PET studies. Overall, these works have confirmed, in humans, the fundamental role of the dopaminergic and opioidergic system on placebo/nocebo as well as the specific areas engaged in the processing of both phenomena, mainly the reward circuitry with its functioning centered in the activity of the NAc. This progress in the understanding of the precise neuromechanisms underlying placebo and nocebo effects can potentially impact the evaluation of clinical trial results, development of therapeutic strategies, and even from a broader perspective, the comprehension of the interindividual variability related to pain experience. The activation of the mu-opioid system in the placebo response was demonstrated in an early PET study. Significant activation of the mu-opioid system was found in the insula, rACC, DLPFC, and NAc.70 More importantly, the mu-opioid system activity was correlated with the pain experience. For instance, the DLPFC mu-opioid activation found in that study was related to the degree of the expected analgesia induced by placebo. Interestingly, the same study applied a system for pain delivery that allowed the measurement of variations in the requirements of the algesic substance used before and after the placebo administration. Therefore, it provided an objective evaluation of changes in pain sensitivity induced by placebo, or in other words, the activation of antinociceptive mechanisms. Mu-opioid activation in the rACC was highly correlated with the requirements of the algesic infusion to keep the pain during the study.70 In fact, the role of rACC in the placebo mechanisms has been shown by other studies.3,22 It has also been demonstrated that the coupling between the ACC and PAG induced by placebo can be blocked by naloxone.22
The investigation of the role of expectations and learning processes to the activation of the mu-opioid system during placebo has revealed that the prediction error signal (eg, the difference between the expected and perceived analgesia) is related to the analgesic responses produced by placebo and to the mu-opioid activation in the ACC, insula, amygdala, thalamus, and OFC.50 In the same study, individuals with low expectations and higher effectiveness (representing a positive prediction error signal) exhibited the strongest placebo responses, whereas subjects with higher expectations and lower effectiveness (eg, negative prediction error signal) displayed nocebo responses.
A further study investigated compared the roles of the opioidergic and dopaminergic systems with the development of placebo and nocebo effects in healthy volunteers.59 Remarkably, nocebo and placebo produced opposite effects in those systems. Activations of both dopaminergic and opioidergic systems were found with placebo while deactivations occurred with nocebo. Placebo-induced activation in the dopaminergic system was found in the basal ganglia, including the NAc. Indeed, the dopaminergic release in the NAc was responsible for 25% of the variance in the analgesic effects produced by placebo. In the opioidergic systems, those effects were also detected in the NAc but extended to other brain regions such as the PAG, amygdala, OFC, insula (anterior and posterior), and ACC (rostral and subgenual). On the other hand, 25% of the sample experienced hyperalgesia with the administration of the placebo, which represented the nocebo effect. Nocebo correlated to deactivation of the dopaminergic and opioidergic systems with plentiful overlap of the brain regions affected by both effects (placebo and nocebo). When comparing placebo-induced changes in the activity of mu-opioid and dopamine neurotransmissions between high placebo and nocebo responders, again, significant deactivations were found in nocebo responders opposing to the activations found in the group of placebo responders. Regarding the mu-opioid neurotransmission, the changes were found in the subgenual ACC, anterior insula, OFC, and thalamus, while in the dopaminergic system, similar findings were detected in the NAc and putamen. Another important finding of that study was that the degree of placebo-induced dopaminergic and opioidergic activations in the NAc predicted high and low placebo responsiveness. Furthermore, the activation of dopamine neurotransmission in the NAc correlated with the degree of mu-opioid activation in regions that responded to placebo. Such findings corroborate the importance of dopamine receptors to the activity of mu-opioid neurotransmission12 as well as the participation of mesolimbic dopaminergic projections and its interactions with the opioidergic system to the placebo analgesia.58 In fact, it has been described that placebo characterizes a type of reward expectation; therefore, both share the same pathways.17
The activation of the mu-opioid system induced by placebo has also been investigated from the perspective of specific clinical conditions and alternative pain treatment modalities. One of those studies investigated the effects of a placebo treatment in patients with episodic migraine during their interictal phase using PET with [11C] diprenorphine. Although the placebo treatment resulted in decreased pain scores, the magnitude of the placebo effect was not significantly different between placebo and controls. Moreover, patients with migraine and healthy controls did not differ regarding activity of opioid receptors induced by placebo.34 As expected, few subjects from each group reported higher pain levels with the placebo treatment. Those individuals were classified as nocebo responders instead of placebo responders. Another study investigated the neuromechanisms related to a method of noninvasive modality of neuromodulation, namely transcranial direct cranial stimulation (tDCS) on healthy subjects through PET.20 The results demonstrated that sham and real stimulation (2 mA for 20 minutes) induced mu-opioid activation in shared (precuneus and PAG) as well as in specific brain regions (the thalamus for sham and the PFC for real tDCS). These data support the presence of a placebo effect contributing to the clinical effects of tDCS. Moreover, those findings suggest that both shared and specific mechanisms underlie the effects of such method. Similar findings have also been demonstrated with other neuromodulatory techniques, such as transcranial magnetic stimulation (TMS), confirming the activation of the mu-opioid system driven by noninvasive methods of neuromodulation.31 More specifically, in a study published by Lamusuo et al.,31 the availability of mu-opioid receptors was lower after real TMS applied to S1/M1 when compared with sham stimulation in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, left insula, superior temporal gyrus, dorsolateral PFC, and precentral gyrus. These results might represent a higher release of endogenous opioids driven by TMS. Another study assessed the availability of opioid receptors, measured through the nonselective radiotracer [11C] diprenorphine, preoperatively and postoperatively, in patients with neuropathic pain treated with motor cortex stimulation (MCS). The results indicated that the levels of opioid receptors assessed through preoperative PET scans may be valuable predictors of MCS outcomes when used to treat neuropathic pain. For instance, in that particular study, patients exhibiting values of opioid receptor density below the lower limits in age-matched controls in the contralateral insula, PAG, and thalamus were presented the lowest probabilities to benefit from MCS treatment.38 An additional PET study also reported a focal release of endogenous opioids driven by deep brain stimulation (DBS) of the PAG. However, those effects were neither affected by the systemic administration of the opioid antagonist naloxone nor correlated to the analgesic effects produced by DBS. Therefore, such findings were not able to determine whether the analgesic effects produced by DBS are indeed driven by a DBS-related opioid release.60 Another study that explored the effects of traditional and sham (placebo) Chinese acupuncture in patients with fibromyalgia26 also suggested differential mechanisms, both involving the mu-opioid neurotransmission, underlying each one.
Interestingly, some studies have indicated that placebo effects and the related mu-opioid activation may be predicted by some personality traits48 and influenced by genetic factors.49 Such information could be extremely useful when designing clinical trials, especially in cases of therapies previously expected to produce large placebo effects. The use of such information would permit the subdivision of clinical pain study samples based on the potential development placebo/nocebo effects and the presence of genetic polymorphisms or personality traits that exert direct influence over the placebo response. Another fact still scarcely explored in the literature is how the degree of placebo responses can predict the effectiveness of nonpharmacological therapies such as cognitive-behavioral therapy or neuromodulatory therapies.51,55
5. Conclusions and perspectives
The possibility of studying the human opioid system in vivo has contributed important information to the understanding of the antinociceptive mechanism related to acute and chronic pain, as well as the neurochemical basis of both placebo and nocebo effects. The altered functioning of the opioid system in the brain of patients with chronic pain represents one of the most important findings obtained with clear therapeutic implications. The interindividual variability in the mu-opioid system activation is another prominent result provided by PET studies. Future studies are expected to expand the overall knowledge regarding the contribution of genetic polymorphisms to the differential responses of the mu-opioid system to pain and to the individual resiliency or susceptibility to chronic pain development. The use of that information, together with the investigation of genetic, potentially inflammatory markers, or even associated personality traits, will be extremely useful in the development of clinical trials with better stratification of the individuals, analyzed based on their expected activation of the mu-opioid system as well as on their predisposition to experience placebo or nocebo effects.
The authors have no conflict of interest to declare.
A.F. DaSilva is funded by the National Institute of Health–National Institute of Neurological Disorders and Stroke—R01 NS094413, and National Institute of Dental and Craniofacial Research—U01 DE025633. M.F. DosSantos is funded by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Jovem Cientista do Nosso Estado (JCNE), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ).
. Afridi SK, Matharu MS, Lee L, Kaube H, Friston KJ, Frackowiak RS, Goadsby PJ. A PET
study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005;128(pt 4):932–9.
. Aimone LD, Jones SL, Gebhart GF. Stimulation-produced descending inhibition from the periaqueductal gray and nucleus raphe magnus in the rat: mediation by spinal monoamines but not opioids
. Amanzio M, Benedetti F. Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 1999;19:484–94.
. Anisman H, Zalcman S, Zacharko RM. The impact of stressors on immune and central neurotransmitter activity: bidirectional communication. Rev Neurosci 1993;4:147–80.
. Apkarian AV, Sosa Y, Sonty S, Levy RM, Harden RN, Parrish TB, Gitelman DR. Chronic back pain
is associated with decreased prefrontal and thalamic gray matter density. J Neurosci 2004;24:10410–5.
. Baliki MN, Geha PY, Fields HL, Apkarian AV. Predicting value of pain
and analgesia: nucleus accumbens response to noxious stimuli changes in the presence of chronic pain
. Neuron 2010;66:149–60.
. Becerra L, Borsook D. Signal valence in the nucleus accumbens to pain
onset and offset. Eur J Pain
. Bencherif B, Fuchs PN, Sheth R, Dannals RF, Campbell JN, Frost JJ. Pain
activation of human supraspinal opioid pathways as demonstrated by [11C]-carfentanil and positron emission tomography (PET
. Berta T, Liu T, Liu YC, Xu ZZ, Ji RR. Acute morphine activates satellite glial cells and up-regulates IL-1β in dorsal root ganglia in mice via matrix metalloprotease-9. Mol Pain
. Brown CA, Matthews J, Fairclough M, McMahon A, Barnett E, Al-Kaysi A, El-Deredy W, Jones AK. Striatal opioid receptor availability is related to acute and chronic pain
perception in arthritis: does opioid adaptation increase resilience to chronic pain
. Casey KL, Minoshima S, Morrow TJ, Koeppe RA. Comparison of human cerebral activation pattern during cutaneous warmth, heat pain
, and deep cold pain
. J Neurophysiol 1996;76:571–81.
. Chen JF, Aloyo VJ, Weiss B. Continuous treatment with the D2 dopamine receptor agonist quinpirole decreases D2 dopamine receptors, D2 dopamine receptor messenger RNA and proenkephalin messenger RNA, and increases mu opioid receptors in mouse striatum. Neuroscience 1993;54:669–80.
. Cohen SP, Mao J. Neuropathic pain
: mechanisms and their clinical implications. BMJ 2014;348:f7656.
. DaSilva AF, Becerra L, Pendse G, Chizh B, Tully S, Borsook D. Colocalized structural and functional changes in the cortex of patients with trigeminal neuropathic pain
. PLoS One 2008;3:e3396.
. DaSilva AF, Granziera C, Snyder J, Hadjikhani N. Thickening in the somatosensory cortex of patients with migraine. Neurology 2007;69:1990–5.
. DaSilva AF, Nascimento TD, DosSantos MF, Lucas S, van Holsbeec KH, DeBoer M, Maslowski E, Love T, Martikainen IK, Koeppe RA, Smith YR, Zubieta JK. Association of mu-opioid activation in the prefrontal cortex with spontaneous migraine attacks—brief report I. Ann Clin Transl Neurol 2014;1:439–44.
. de la Fuente-Fernández R, Ruth TJ, Sossi V, Schulzer M, Calne DB, Stoessl AJ. Expectation and dopamine release: mechanism of the placebo effect in Parkinson's disease. Science 2001;293:1164–6.
. Denuelle M, Fabre N, Payoux P, Chollet F, Geraud G. Hypothalamic activation in spontaneous migraine attacks. Headache 2007;47:1418–26.
. Dossantos MF, Martikainen IK, Nascimento TD, Love TM, Deboer MD, Maslowski EC, Monteiro AA, Vincent MB, Zubieta JK, Dasilva AF. Reduced basal ganglia mu-opioid receptor availability in trigeminal neuropathic pain
: a pilot study. Mol Pain
. DosSantos MF, Martikainen IK, Nascimento TD, Love TM, DeBoer MD, Schambra HM, Bikson M, Zubieta JK, DaSilva AF. Building up analgesia in humans via the endogenous mu-opioid system by combining placebo and active tDCS: a preliminary report. PLoS One 2014;9:e102350.
. DosSantos MF, Moura BS, DaSilva AF. Reward circuitry plasticity in pain
perception and modulation. Front Pharmacol 2017;8:790.
. Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, Büchel C. Activation of the opioidergic descending pain
control system underlies placebo analgesia. Neuron 2009;63:533–43.
. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpää M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain
in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73.
. Granziera C, DaSilva AF, Snyder J, Tuch DS, Hadjikhani N. Anatomical alterations of the visual motion processing network in migraine with and without aura. PLoS Med 2006;3:e402.
. Harris R, Clauw D, Scott D, McLean S, Gracely R, Zubieta J. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci 2007;27:10000–6.
. Harris RE, Zubieta JK, Scott DJ, Napadow V, Gracely RH, Clauw DJ. Traditional Chinese acupuncture and placebo (sham) acupuncture are differentiated by their effects on mu-opioid receptors (MORs). Neuroimage 2009;47:1077–85.
. Iwaszkiewicz KS, Schneider JJ, Hua S. Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions. Front Pharmacol 2013;4:132.
. Jones AK, Cunningham VJ, Ha-Kawa S, Fujiwara T, Luthra SK, Silva S, Derbyshire S, Jones T. Changes in central opioid receptor binding in relation to inflammation and pain
in patients with rheumatoid arthritis. Br J Rheumatol 1994;33:909–16.
. Karjalainen T, Karlsson HK, Lahnakoski JM, Glerean E, Nuutila P, Jääskeläinen IP, Hari R, Sams M, Nummenmaa L. Dissociable roles of cerebral μ-opioid and type 2 dopamine receptors in vicarious pain
: a combined PET
-fMRI study. Cereb Cortex 2017;27:4257–66.
. Knight YE, Goadsby PJ. The periaqueductal grey matter modulates trigeminovascular input: a role in migraine? Neuroscience 2001;106:793–800.
. Lamusuo S, Hirvonen J, Lindholm P, Martikainen IK, Hagelberg N, Parkkola R, Taiminen T, Hietala J, Helin S, Virtanen A, Pertovaara A, Jääskeläinen SK. Neurotransmitters behind pain
relief with transcranial magnetic stimulation—positron emission tomography evidence for release of endogenous opioids
. Eur J Pain
. Ledermann K, Jenewein J, Sprott H, Hasler G, Schnyder U, Warnock G, Johayem A, Kollias S, Buck A, Martin-Soelch C. Relation of dopamine receptor 2 binding to pain
perception in female fibromyalgia patients with and without depression—a [11
C] raclopride PET
-study. Eur Neuropsychopharmacol 2016;26:320–30.
. Levine JD, Gordon NC, Fields HL. The mechanism of placebo analgesia. Lancet 1978;2:654–7.
. Linnman C, Catana C, Petkov MP, Chonde DB, Becerra L, Hooker J, Borsook D. Molecular and functional PET
-fMRI measures of placebo analgesia in episodic migraine: preliminary findings. Neuroimage Clin 2018;17:680–90.
. Loggia ML. Chronic pain
and opioid receptor availability: disentangling the molecular contributions and the “chicken or the egg” dilemma. PAIN
. Ly HG, Dupont P, Geeraerts B, Bormans G, Van Laere K, Tack J, Van Oudenhove L. Lack of endogenous opioid release during sustained visceral pain
: a [11C]carfentanil PET
. Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, Laurent B, Garcia-Larrea L. Differential brain opioid receptor availability in central and peripheral neuropathic pain
. Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, Laurent B, Garcia-Larrea L. Brain opioid receptor density predicts motor cortex stimulation efficacy for chronic pain
. Majuri J, Joutsa J, Johansson J, Voon V, Alakurtti K, Parkkola R, Lahti T, Alho H, Hirvonen J, Arponen E, Forsback S, Kaasinen V. Dopamine and opioid neurotransmission in behavioral addictions: a comparative PET
study in pathological gambling and binge eating. Neuropsychopharmacology 2017;42:1169–77.
. Mason P. Ventromedial medulla: pain
modulation and beyond. J Comp Neurol 2005;493:2–8.
. Melzack R. Pain
—an overview. Acta Anaesthesiol Scand 1999;43:880–4.
. Melzack R, Casey K. Sensory, motivational and central control determinants of pain
: a new conceptual model. In: Kenshalo DR, editor. The skin senses: Thomas, Springfield, 1968. pp. 423–43.
. Merskey H, Bogduk N, International Association for the Study of P. Classification of chronic pain
: Descriptions of chronic pain
syndromes and definitions of pain
terms. Seattle: IASP Press, 1994.
. Nascimento T, Yang N, Salman D, Jassar H, Bellile E, Koeppe R, Stohler C, Zubieta J, Ellingrod V, DaSilva A. COMT genotype modulates endogenous μ-opioid system and pain
sensitivity in TMD world congress on pain
. Boston: International Association for the Study of Pain
. Nascimento TD, DosSantos MF, Lucas S, van Holsbeeck H, DeBoer M, Maslowski E, Love T, Martikainen IK, Koeppe RA, Smith YR, Zubieta JK, DaSilva AF. mu-Opioid activation in the midbrain during migraine allodynia—brief report II. Ann Clin Transl Neurol 2014;1:445–50.
. Nees F, Becker S, Millenet S, Banaschewski T, Poustka L, Bokde A, Bromberg U, Büchel C, Conrod PJ, Desrivières S, Frouin V, Gallinat J, Garavan H, Heinz A, Ittermann B, Martinot JL, Papadopoulos Orfanos D, Paus T, Smolka MN, Walter H, Whelan R, Schumann G, Flor H; IMAGEN Consortium. Brain substrates of reward processing and the ì-opioid receptor: a pathway into pain
. Nuechterlein EB, Ni L, Domino EF, Zubieta JK. Nicotine-specific and non-specific effects of cigarette smoking on endogenous opioid mechanisms. Prog Neuropsychopharmacol Biol Psychiatry 2016;69:69–77.
. Peciña M, Azhar H, Love TM, Lu T, Fredrickson BL, Stohler CS, Zubieta JK. Personality trait predictors of placebo analgesia and neurobiological correlates. Neuropsychopharmacology 2013;38:639–46.
. Peciña M, Martínez-Jauand M, Hodgkinson C, Stohler CS, Goldman D, Zubieta JK. FAAH selectively influences placebo effects. Mol Psychiatry 2014;19:385–91.
. Peciña M, Stohler CS, Zubieta JK. Neurobiology of placebo effects: expectations or learning? Soc Cogn Affect Neurosci 2014;9:1013–21.
. Pecina M, Zubieta JK. Expectancy modulation of opioid neurotransmission. Int Rev Neurobiol 2018;138:17–37.
. Prossin AR, Zalcman SS, Heitzeg MM, Koch AE, Campbell PL, Phan KL, Stohler CS, Zubieta JK. Dynamic interactions between plasma IL-1 family cytokines and central endogenous opioid neurotransmitter function in humans. Neuropsychopharmacology 2015;40:554–65.
. Quelch DR, Katsouri L, Nutt DJ, Parker CA, Tyacke RJ. Imaging endogenous opioid peptide release with [11C]carfentanil and [3H]diprenorphine: influence of agonist-induced internalization. J Cereb Blood Flow Metab 2014;34:1604–12.
. Ruzicka BB, Akil H. The interleukin-1beta-mediated regulation of proenkephalin and opioid receptor messenger RNA in primary astrocyte-enriched cultures. Neuroscience 1997;79:517–24.
. Schambra HM, Bikson M, Wager TD, DosSantos MF, DaSilva AF. It's all in your head: reinforcing the placebo response with tDCS. Brain Stimul 2014;7:623–4.
. Schrepf A, Harper DE, Harte SE, Wang H, Ichesco E, Hampson JP, Zubieta JK, Clauw DJ, Harris RE. Endogenous opioidergic dysregulation of pain
in fibromyalgia: a PET
and fMRI study. PAIN
. Scott DJ, Heitzeg MM, Koeppe RA, Stohler CS, Zubieta JK. Variations in the human pain
stress experience mediated by ventral and dorsal basal ganglia dopamine activity. J Neurosci 2006;26:10789–95.
. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 2007;55:325–36.
. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008;65:220–31.
. Sims-Williams H, Matthews JC, Talbot PS, Love-Jones S, Brooks JC, Patel NK, Pickering AE. Deep brain stimulation of the periaqueductal gray releases endogenous opioids
in humans. Neuroimage 2017;146:833–42.
. Stankewitz A, Aderjan D, Eippert F, May A. Trigeminal nociceptive transmission in migraineurs predicts migraine attacks. J Neurosci 2011;31:1937–43.
. Thompson SJ, Pitcher MH, Stone LS, Tarum F, Niu G, Chen X, Kiesewetter DO, Schweinhardt P, Bushnell MC. Chronic neuropathic pain
reduces opioid receptor availability with associated anhedonia in rat. PAIN
. Tölle TR, Kaufmann T, Siessmeier T, Lautenbacher S, Berthele A, Munz F, Zieglgänsberger W, Willoch F, Schwaiger M, Conrad B, Bartenstein P. Region-specific encoding of sensory and affective components of pain
in the human brain: a positron emission tomography correlation analysis. Ann Neurol 1999;45:40–7.
. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, Kosslyn SM, Rose RM, Cohen JD. Placebo-induced changes in FMRI in the anticipation and experience of pain
. Science 2004;303:1162–7.
. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human mu-opioid activity during pain
. Proc Natl Acad Sci USA 2007;104:11056–61.
. Wei SY, Chen LF, Lin MW, Li WC, Low I, Yang CJ, Chao HT, Hsieh JC. The OPRM1 A118G polymorphism modulates the descending pain
modulatory system for individual pain
experience in young women with primary dysmenorrhea. Sci Rep 2017;7:39906.
. Wey HY, Catana C, Hooker JM, Dougherty DD, Knudsen GM, Wang DJ, Chonde DB, Rosen BR, Gollub RL, Kong J. Simultaneous fMRI-PET
of the opioidergic pain
system in human brain. Neuroimage 2014;102(pt 2):275–82.
. Willoch F, Schindler F, Wester HJ, Empl M, Straube A, Schwaiger M, Conrad B, Tölle TR. Central poststroke pain
and reduced opioid receptor binding within pain
processing circuitries: a [11C]diprenorphine PET
. Zhang Y, Wang D, Johnson AD, Papp AC, Sadée W. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A118G. J Biol Chem 2005;280:32618–24.
. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, Nichols TE, Stohler CS. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005;25:7754–62.
. Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA, Koeppe RA. Regulation of human affective responses by anterior cingulate and limbic mu-opioid neurotransmission. Arch Gen Psychiatry 2003;60:1145–53.
. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS. Regional mu opioid receptor regulation of sensory and affective dimensions of pain
. Science 2001;293:311–5.
. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, Stohler CS. mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 2002;22:5100–7.
. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain
stressor. Science 2003;299:1240–3.
. Zubieta JK, Stohler CS. Neurobiological mechanisms of placebo responses. Ann N Y Acad Sci 2009;1156:198–210.

domain: literature


text:
Etna, hiking to the summit craters
Let's experience Mount Etna and reach its summit. At 2000 m, with cable car, 4WD bus, and expert guide, we will reach 2900 meters of altitude. We will walk on a moonscape soil to the summit craters of the highest active volcano in Europe surrounded by a unique panorama.
The hiking tour starts from Piazzale Dei Crateri Silvestri at 2000 m, with cable car and a 4x4 bus we will reach 2900 meters up to the Torre del Filosofo refuge. During the two-hour hiking, we will stop 2-3 times to admire the stunning landscape. We will walk through moonscape sceneries of ancient lava eruption that will accompany us until the discovery of the summit craters. We will resume the walk on Etna for another two hours until reaching the upper cable-car station. This grand tour of Etna will allow us to learn about the history of one of the most famous volcanoes in the world, present for 60 million years, described for centuries in the books of literature and symbol of Sicily. Along the way, the expert guide will tell us its story from the origin to today, and the aspects related to the fauna and flora that characterize this landscape rarity. This experience is suitable for hikers with proper physical preparation for exposed tracks and uneven ground.

domain: hobby


text:
Abstract 281: Cytostatic Gene, l-Caldesmon, Suppressed Proliferation and Migration of Vascular Smooth Muscle Cells and Inhibits Neointimal Formation by Regulating the FAK-ERK Axis
Light type-caldesmon (l-CaD) is a cytostatic gene which is induced after mechanical stimuli to regulate cell growth and survival via modulation of cell shape and cytoskeleton. The aim of this study is to evaluate the inhibitory effect of l-CaD on neointimal formation after angioplasty like other cytostatic agents such as rapamycin and paclitaxel, which are predominantly used for drug eluting stents. Methods and Results: We tested cytostatic functions of l-CaD in human vascular smooth muscle cells (VSMCs) using assays for apoptosis, cell proliferation, and migration, and evaluated the expression pattern of each marker protein (focal adhesion kinase (FAK) and MAPKs) in VSMCs. Transfection of adenoviral vector encoding l-CaD (Ad-l-CaD) resulted in progressive loss of actin stress fibers and cell retraction. WST-1 proliferation assay demonstrated that l-CaD overexpression gradually decreased cell proliferation rate by 78% in VSMCs over 72 hours(p=0.011, n=6). ELISA demonstrated that Ad-l-CaD transfection increased the apoptosis rate by 75% in accordance with inhibition of bcl-2 expression and upregulation of caspase-3 activity, and reduced BrdU uptake by 49% (p=0.012, n=4 each vs. control of GFP alone). Furthermore, transfection of Ad-l-CaD inhibited migration of VSMCs induced by platelet-derived growth factor-BB (PDGF) by 36% (p=0.031, n=4). Immunoblotting analysis revealed that l-CaD overexpression reduced PDGF-induced phosphorylation of both FAK and extracellular signal regulated-kinase (ERK), but no significant reduction was seen in p38MAPK and SAPK/JNK. In balloon-injured rat carotid arteries, Ad-l-CaD transfection inhibited neointimal formation by 37% (Table⇓, p=0.042, n=6 each) without delaying reendothelializa-tion and thrombus occlusion at 14 days. Conclusions: Overexpression of l-CaD suppressed cell growth and survival in VSMCs and inhibited neointimal formation after experimental angio-plasty, partly by regulating the FAK-ERK axis.


text:
Air: Moon Safari LP
In correlation with The Virgin Suicides: 15th Anniversary Deluxe Edition box set and 180g vinyl reissue, Warner/Parlophone will also be releasing Air's five album discography on remastered 180-gram vinyl with original artwork, including their first EP Premiers Symptômes (1997), Moon Safari (1998), 10,000 Hz Legend (2001), Talkie Walkie (2004) and Pocket Symphony (2007).
1998's Moon Safari is the acclaimed full-length debut from French postmodern electro duo Air - acronym for "Amour, Imagination, Reve" (love, imagination, dream) - comprised of sound auteurs Nicolas Godin and Jean-Benoit Dunckel. The pair originally recorded Moon Safari's basic tracks on a Fostex D80 in Saint-Nom and then flushed the songs out in Gang Studios in Paris while the album's strings were arranged by music legend David Whitaker at Abbey Road in London.
Highlighted by lush arrangements and the stylistic electronic compositions "Sexy Boy" and "Kelly Watch the Stars," Moon Safari's ethereal space-pop not only put Air on the musical map, but it distinguished the duo as gifted musicians and songwriters who only sounded like producers.


Our Municipal Separate Storm Sewer System (MS4) discharges stormwater into more than 30 waterways and wetlands within the Municipality of Anchorage (Municipality) and in State of Alaska rights-of-way owned or operated by the Alaska Department of Transportation and Public Facilities (DOT&PF). The National Pollutant Discharge Elimination System (NPDES) Program originated under section 402 of the Clean Water Act (CWA, 33 USC §1251), which requires that pollutant discharges to surface water be authorized by permit. Together, the Municipality and the DOT&PF are authorized to do so through an Authorization to Discharge under the National Pollutant Discharge Elimination System. This authorization, Alaska Pollutant Discharge Elimination System (APDES) Permit No. AKS 05255-8, is effective from August 1, 2015 to July 31, 2020. The Term III APDES permit required an update to the Quality Assurance Plan (QAP).
The APDES Permit also allows discharge of certain non-stormwater flows, as well as stormwater discharge associated with industrial activity and construction. It outlines compliance responsibilities, limitations, and the requirement of a Stormwater Management Program. The permit incorporates a schedule for compliance, and outlines strict monitoring, record keeping, and reporting requirements. Civil, administrative, and even criminal penalties can apply if the conditions of the permit are not met.
2019 Annual Meeting
The 2019 APDES Annual Meeting was held on Wednesday, February 27th at the BP Energy Center. This year, the format for the meeting was an open house and included a poster display session with breakout discussions on permit related topics. An agenda for the meeting is availible here. The 2020 Annual Meeting will be held on February 26th. If you would like more information on the Annual Meeting, please contact us at 907-343-8135.
Read our 2018 APDES Annual Report for more detailed information about the permit and actions taken to meet permit requirements. The 2018 Annual Report was submitted to the Alaska Department of Conservation on February 15th, 2019. Last year's annual report can be found HERE.
|2018 APDES Annual Report
|2018 APDES Annual Report Certification Documents