CRPS – Skeletal Cannabinoid System – Immune System

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What I’m really interested in is the Skeletal Cannabinoid System.

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We know cannabinoid receptors outnumber every receptor type in the human body.

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Cannabindoids are located primarily in immune tissue. 

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Perhaps one reason we have not found more insight into neuropathic pain, complex regional pain syndrome, is because we have not seriously looked at the cannabinoid system. It is the largest receptor system in the body and it is located in immune tissue. Our brain makes endocannabinoids like Anandamide, that relieve pain, that are made by glial tissue, which is immune tissue. And they relieve many other symptoms and life threatening seizures as well. Pain and depression are my key interests.

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Quoting from Nephi Stella:

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“Cannabinoids, the bioactive components produced by the marijuana plant Cannabis Sativa, have immunomodulatory properties that are quite distinct from currently available immunomodulatory drugs.”

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So, back to the Skeletal Endocannabinoid Sytem, please let me know of any references to the Skeletal Endocannabinoid system, especially key articles or a review of that system, or has access to funding and to Professor Mechoulam’s lab, so we could see some research funded in order to learn about this. I welcome comments with publications and references, below.

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Even if we could get more funding for regenerative research in bone, it may lead to discovery of a mechanism involved in the osteoporosis with CRPS or senility.

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Cannabinoids

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First, let me say I am not endorsing use of cannabinoids unless you have a full understanding of contraindications, and yes it can be dangerous if you have those conditions. That’s why I built a cannabis website in 2009. I cannot remember the scientific details I studied, but there were over 17,000 publications when I put that up. I had to build the website to educate myself, and be able to “put it together, to grasp it and learn it and be able to link back. It was a huge data base to reference after doing my analysis. Alas, I had to scrub most of it because it is illegal even to write about certain things or link to a video. It’s sad that doctors get persecuted for prescribing cannabis for desperate conditions. It’s sad it cannot be made legal for the poor and middle class to use responsibly and recreationally.

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Dr. Nephi Stella at University of Washington studies deep cannabinoid brain science:

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He was an invited speaker at an RSDSA sponsored conference in 2010  on glia. They convened what may be the largest number of most distinguished glial scientists in the world working on translational issues, translating science to the clinic as it relates to pain. Glial cells are important for inflammation and pain, depression, almost every known condition. As for glia, one of the endocannabinoids that your brain makes, is made by a glial cell, and reabsorbed by the cell.

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Dr. Stella’s faculty page reads:

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How can the medicinal properties of marijuana be improved to treat neurodegenerative diseases?

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The brain, being isolated from the rest of the body by the blood brain barrier, has its own specialized immune system consisting of the interplay between glial cells and small numbers of patrolling immune cells. This “brain specific immune system” is similar to the peripheral immune system in its ability to both destroy foreign agents and repair injured tissue, though it does so with much less efficacy. Indeed, while the brain’s immune system can probably cope with minor insults and infections, its unable to mount effective responses against more devastating neuropathological processes….

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Remarkably, these neuropathological processes are often associated with dysfunctional glial cells, limiting their ability to repair injured neurons and actually rendering them more hostile against healthy neurons. Thus, a promising therapeutic approach for the aforementioned neurodegenerative diseases is to develop pharmacological agents that target glial cells to reinstate their reparative function while tempering their hostility.
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My laboratory is interested in identifying the molecular machinery controlling changes in glial cell phenotype, with the aim of developing pharmacological tools that will minimize their harmful phenotype and reinstate – or even boost – their reparative function. Our current most promising target is the endocannabinoid signaling system.
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Cannabinoids, the bioactive components produced by the marijuana plant Cannabis Sativa, have immunomodulatory properties that are quite distinct from currently available immunomodulatory drugs. These compounds act through specific receptors named CB1 and CB2. CB1 receptors are expressed by neurons and mediate the drug of abuse properties of marijuana, while CB2 receptors are expressed by immune and glial cells and mediate its immunomodulatory properties. This dichotomy has tremendous therapeutic potential since it allows for the development of agents that specifically target CB2 receptors and thus regulate immune functions without inducing the drug of abuse adverse effects mediated through CB1 receptors. Cannabinoid receptors are normally activated by endogenous ligands, the endocannabinoids.
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We are currently testing the hypothesis that agents acting through CB2 receptors or blocking the degradation of endocannabinoids can temper the detrimental inflammatory responses occurring in Huntington’s disease, AIDS dementia and multiple sclerosis. We chose to study these pathologies because they remain without cure and thus demand regimented scientific efforts to relieve these patients. We are also using genetic and proteomics approaches to identify novel cannabinoid receptors and enzymes degrading endocannabinoids, with the hope that such proteins constitute promising targets for therapy. Our goal is to identify cannabinoid-based targets and agents devoid of drug of abuse properties that provide treatment of diverse neuropathologies.

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This field has been largely ignored for almost the entire 20th century. Even when it was discovered it is a major player in the immune system and so many systems it is yet to be discovered where and why.

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Nephi, if you are reading this, thank you for working with glia and the cannabinoid system!

Congratulations on your work!

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I know some of you ignore this, but I have to repeat:

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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.

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This material is not a substitute for medical advice, diagnosis or treatment provided

by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

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For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Side Effects of Neridronic Acid – Neridronate

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Neridronate

Neridronic acid

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This is a long response to detailed comments from Julie who had a reaction to the neridronic acid protocol for CRPS.

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The clinical trial on neridronic acid is extremely important and unique. It is important because it does not just cover symptoms, it actually may put CRPS into remission.

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If I had CRPS, I would not hesitate to accept short term side effects if I thought I could get long term benefit, even possibly remission. We need this study. It will not be available for anyone unless many enroll in the double blind study and hopefully soon so that results can be submitted to the FDA for approval.

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Please read her comments first, at the end of my post. And then my comments below.

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And because neridronic acid relates to bone metabolism, much later I will mention an area of research that is likely to be be valuable because it is the largest receptor system in the body, the endocannabinoid receptor system, the body’s own cannabinoid system.  Two ideas from Raphael Mechoulam, professor of Medicinal Chemistry at the Hebrew University of Jerusalem in Israel are keenly interesting:

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The Skeletal Endocannabinoid System

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The Entourage Effect

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Glia make one of the cannabinoids in the brain, and glial research is where I suspect some of the best research will come

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Hopefully these ideas will stimulate  research.

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In response to Julie, I wrote:

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Julie, I am so sorry to hear of the difficulty you had to go through for such a long time. And relieved that you got through it. I and, I’m sure everyone else, thanks you for volunteering. We will all benefit. And we all hope that if any reaction is to occur, please let it be rare. It appears that yours is rare.

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I know everyone is with you, and we bring all our hopes for the unknown. No one has the answer of what to do with intractable pain of any kind, not just CRPS pain. We must, MUST, begin to do more research on intractable pain in humans. Neridronic acid is an important beginning to look at a new mechanism.

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CRPS has, in some people, escaped every known rational approach to treatment. Neridronate may be the best thing we can get. It takes time to learn how new medications work, and they have chosen wisely, I am sure.

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Be assured, I think good minds are working on the best. But it is unknown territory.  Numbers are needed – CRPS can be very dynamic. Flares and remissions wax and wane, so long term study must be done.

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We all see patients after CRPS flares and there is nothing more to offer. Not one thing. We urgently need something that works. We are hoping neridronic acid will be that rescue.

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Will remission last 12 months or 3 months or less?

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What are long term risks?

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How often could it potentially be given, or will remission really last for years in some? We all need to see numbers.

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Huge hopes are on this drug.

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We must balance hopes and fears.

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We recognize it is a new drug for a new purpose. We hope this research will drive many more studies on CRPS and/or intractable pain.

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Julie, thank you for allowing others to see details. It may help other volunteers to set aside time to recover any post infusion effects, if needed. Hope for the best, plan for the worst is the saying.

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No one yet knows how good the potential is for duration of effect. Remission could potentially be total, in some. How many?

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We are all learning how to treat chronic intractable pain.

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Skeletal Endocannabinoid System

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The highly decorated scientist who discovered THC and the body’s endocannabinoid system, Raphael Mechoulam, professor of Medicinal Chemistry at the Hebrew University of Jerusalem, recently mentioned the SKELETAL CANNABINOID SYSTEM in a 2014 documentary on his discoveries.

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The cannabinoid system interacts powerfully with the immune system in ways not yet studied. Why does your CRPS immune system affect the skeletal system and create pain?

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Cannabinoids are anti-inflammatory, analgesic, healing. The body makes its own. We need to study the biggest receptor system in the body. It is a gaping hole that is left out of existing work on the immune system.

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And how much are glia and our innate immune system in CNS— how much are they studied?

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Please let there somehow be funding for many studies on humans – but let’s begin one study, guided by Distinguished Professor Linda Watkin’s lab. She is the only scientist who is doing translational work from  basic research in the lab to humans.

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Professor Watkins has the best clinical solution I have seen: IL-10 has remarkable potential to bring your pain to zero for 3 months or more at a times. Your brain makes it. It is *the* anti-inflammatory cytokine. Her lab has been the world leader in glial research. Where is the funding for what may be the most important area of work for intractable mood disorders and treatment resistant depression?

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Glia

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How do hundreds of now usable drugs create pro-inflammatory cytokines thus make more pain or more major mood disorder?

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And which of these hundreds of drugs on our formulary reduce inflammatory cytokines?

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What is the role, if any, of some of the medications used by rheumatologists to dampen the hyperactive immune system in autoimmune disease? Risks, but possible gain. We will never have all the answers. ALL the answers for everyone is hard to imagine.

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How do hundreds of existing drugs affect the balance of CNS cytokines?

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Skeletal Endocannabinoid System – see Raphael Machoulam’s lab in Israel. May be critical for CRPS and for osteoporosis in seniors.

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Mechoulam’s lab would bite at the chance to get funded to work with the Italian and USA CRPS study.

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Julie — I am heartened that you may be able to see Professor Ott who may be one of the foremost researchers on bone metabolism if not number one.

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I posted three times on bisphosphonates last year and hope they are a good review for others.

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The Entourage Effect

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Mechoulam also has an important concept that probably applies to my method of trying to modulate these powerful intractable pain syndromes.

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Simple concept – brilliant:

The Entourage Effect. Drugs are like politicians. A famous politician may walk unrecognized, but when you surround him or her with many people, even of lesser status, the politician has a far more powerful effect.

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I don’t know how you guys do it.

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Respectful best wishes.

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I know some of you ignore this, but I have to repeat:

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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.

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This material is not a substitute for medical advice, diagnosis or treatment provided

by a qualified health care provider.

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This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

~~~~~

For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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CRPS Research Funded by RSDS: An Exploratory Study of Genetic, Epigenetic, Proteomic, Metabolomic, and Gene Expression- Related Factors in CRPS

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An Exploratory Study of Genetic,

Epigenetic, Proteomic, Metabolomic, and

Gene Expression- Related Factors in CRPS

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This is one of several studies funded by RSDS. Click on the blue link above to read the full announcement, page 15 of their newsletter today.

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It is always exciting to see what the nonprofit Reflex Sympathetic Dystrophy Syndrome Asssociation does with the money donated to them and then chosen for awards by their distinguished board of scientific advisors.

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Please donate to RSDSA.

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Use the links at top of this page if you like, or their website, but please donate. No one else is actively funding research on Complex Regional Pain Syndrome – research that applies to all forms of neuropathic pain. .It takes constant effort, fund raising and awareness.

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Please donate and ask others to donate to RSDSA.

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If you know anyone with pain, not only pain from CRPS but any pain, please donate. Remember it is almost a certainty that one day you or someone you love will one day have pain. Treatment for chronic intractable pain applies to everyone, not just those with CRPS. Can you spare $4.00 for a coffee? Donate that.

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“In June 2015, the RSDSA awarded a $57,000 grant to Vanderbilt University Medical Center Professor Stephen Bruehl to conduct a study to discover possible genetic and molecular factors related to CRPS.”

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“Why do some develop CRPS and others do not, despite experiencing similar injuries?”.

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“… Dr. Bruehl will analyze a vast amount of highly detailed genetic, protein-related, and metabolism-related information collected as part of a previously completed Department of Defense research study of 116 military veterans experiencing CRPS and non-CRPS pain following traumatic injuries that required limb amputation. This information has never previously been examined.

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Specifically, Dr. Bruehl and his team will study whether development of CRPS rather than non-CRPS limb pain (or no pain) after amputation is linked to differences in:

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•  genetics (particularly in genes not previously explored for CRPS risk)
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• gene expression (whether certain genes are turned on or off)
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• epigenetic regulation (nonpermanent modifications to genes that govern their activity)
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• the proteins that make up the body
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• and how chemicals are metabolized (processed) by the body.

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Dr. Bruehl’s team will also test whether severity of CRPS symptoms is associated with these factors.”

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The material on this site is for informational purposes only.
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It is not legal for me to provide medical advice without an examination.

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It is not a substitute for medical advice, diagnosis or treatment provided

by a qualified health care provider.

~~
This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

~~~~~

For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Analgesic Response to Ketamine Linked to Circulating microRNA in Complex Regional Pain Syndrome

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Analgesic Response to Intravenous Ketamine

Is Linked to a Circulating microRNA Signature

in Female Patients

With Complex Regional Pain Syndrome

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The ability to measure Micro RNS’s (miRNA) in blood looks like it may become an important tool someday once it is available for the clinic. It could be used to predict if your condition will respond to various medications.

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MicroRNAs are emerging as important modulators of various psychiatric (schizophrenia, bipolar disorder) and neurological conditions including pain, epilepsy, cognitive dysfunction, neuronal development, structure and function. “MicroRNAs are small, non-coding RNAs that act as post-transcriptional regulators of gene expression.“  miRNA’s can be affected by morphine and affected by other drugs. It is hoped that complex clinical phenotypes may be profiled in assays of peripheral blood and may predict response to treatment such as in this study. Ketamine is given for selected patients that have failed to respond to standard treatment.

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This research was published in Pain, June 2015, by Professor Schwartzman’s group at Drexel University. Seven of his patients with Complex Regional Pain Syndrome were ketamine responders and 6 were poor responders. They note that, “Although [ketamine] treatment is generally effective, approximately 30% of patients have an inadequate response to ketamine.”

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“Stability in circulation and dysregulation in disease state are 2 features making extracellular miRNAs useful candidates for biomarker discovery. Alterations in miRNA profiles have been reported for rheumatoid arthritis and systemic lupus erythematosus as well as for painful conditions such as irritable bowel syndrome, chronic bladder syndrome, endometriosis, and migraine. Cerebrospinal fluid from patients with fibromyalgia showed differential expression of 9 miRNAs.”

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Quoting directly from the article:

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Highlights

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•We studied ketamine treatment–induced miRNA alterations in blood from patients with CRPS.
•Differential miRNA expression was observed in whole blood before and after treatment.
•Before therapy, 33 miRNAs differed between responders and poor responders.
•Lower pretreatment levels of miR-548d-5p may contribute to higher UDP-GT activity.
•Circulating miRNAs can be potential biomarkers in predicting treatment response.

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From the Abstract

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Investigation of the mechanistic significance of hsa-miR-548d-5p downregulation in poor responders showed that this miRNA can downregulate UDP-glucuronosyltransferase UGT1A1 mRNA. Poor responders had a higher conjugated/unconjugated bilirubin ratio, indicating increased UGT1A1 activity. We propose that lower pretreatment levels of miR-548d-5p may result in higher UDP-GT activity, leading to higher levels of inactive glucuronide conjugates, thereby minimizing the therapeutic efficacy of ketamine in poor responders.

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Perspective

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This study suggests the usefulness of circulating miRNAs as potential biomarkers. Assessing miRNA signatures before and after treatment demonstrated miRNA alterations from therapy; differences in miRNA signature in responders and poor responders before therapy indicate prognostic value. Mechanistic studies on altered miRNAs can provide new insights on disease.

 

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From the Discussion

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Ketamine is also considered to be the prototype for a new generation of glutamate- based antidepressants that can alleviate depression within hours of treatment. Several biological measures have been explored to characterize treatment response and to gain insight into mechanisms underlying the rapid antidepressant effects of ketamine. A plasma metabolomics study in patients with bipolar depression suggested that the basal mitochondrial b-oxidation of fatty acids differed between responders and nonresponders to ketamine. Other studies have shown differences in baseline plasma concentrations of D-serine, serum levels of interleukin 6, and plasma levels of Shank3, a postsynaptic density protein involved in NMDA receptor tethering and dendritic spine rearrangement.

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Differences in the ability to metabolize ketamine because of interindividual differences and pharmacogenetic factors have been proposed to contribute to the varied responses to ketamine therapy and its clinical outcome. Similar conclusions have been drawn for patients with depression; plasma from patients with treatment- resistant bipolar depression who had undergone a single 40-minute infusion of a subanesthetic dose of ketamine showed that although NK is an initial metabolite, it is not the major circulating metabolite. This again suggests that other downstream metabolites of ketamine may play a role in the pharmacological effects of the drug. It is also known that (2S,6S)-hydroxynorketamine is an active and selective inhibitor of the a7 subtype of the nicotinic acetylcholine receptor; this activity was shown to contribute to the pharmacological responses associated with the antidepressant activity of (R,S)-ketamine. We postulate that in patients with CRPS, 1 factor contributing to resistance is an altered pharmacokinetic profile produced by enhanced elimination of active metabolites downstream of NK, which is mediated by hsa-miR-548d-5p. However, because we have relied on indirect evidence of a higher percentage of direct/indirect bilirubin in poor responders, indicating increased UDP-GT enzyme activity, additional studies investigating hydroxynorketamine and its downstream metabolites along with their glucuronide conjugates in plasma and urine will provide direct evidence for the role of miR-548d-5p in mediating response to ketamine therapy in responders and poor responders.

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They noted a significant difference in body weight between responders and nonresponders (heavier), but not in duration of disease and analgesic response to ketamine. Toward that end, they will publish separately upon

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… investigating the link between miR-34a, which showed 28-fold reduction in poor responders relative to responders (Table 2), and the neuroendocrine system….

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From the Conclusion

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Our studies showed that miR-548d-5p can regulate UDP-GT but not CYP3A4, suggesting that UDP-GT activity in responders and poor responders may be mediated by differences in the level of circulating miR-548d-5p. Lower levels of miR-548d-5p in poor responders before treatment could result in higher UDP-GT activity, leading to the production of more inactive glucuronide conjugates and faster elimination of active ketamine metabolites downstream of NK. Thus, the levels of hsa-miR-548d-5p could minimize the therapeutic efficacy of ketamine and pain relief. Differences in miRNA signature can thus provide molecular insights distinguishing responders from poor responders. High failure rates of drugs targeted to treat neuropathic pain warrant changes in approaches. Studies targeting well-defined patient populations for clinical trials will play a crucial in developing drugs that may be efficacious in a subset of patients. Extending this approach to other treatment and outcome assessments might permit stratification of patients for maximal therapeutic outcome.

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How frustrating it is for patients and family who must cope with an intractable condition such as pain or Bipolar Disorder or treatment resistant Major Depression that has failed all commonly prescribed medications. For all of them, we need changes in approach.

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“High failure rates of drugs targeted

to treat neuropathic pain

warrant changes in approaches.”

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Perhaps scientists reading this would comment upon how it may relate to tolerance as it differentially occurs in those receiving intermittent ketamine vs continuous intravenous infusion.

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Dysregulation of miRNA’s has been shown in psychiatric disorders including depression and schozophrenia, neurodevelopmental disorders, cognitive dysfunction,  epilepsy, chronic pain states with implication for the cause and treatment of these disorders.

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Research targeting miRNA’s as novel treatment for depression has shown that chronic fluoxetine, repeated electroconvulsive shock therapy, and acute ketamine have the capacity to alter hippocampal miRNA levels.

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It is hoped these tests may be available someday clinically as the cost of off-label treatment not covered by insurance is a great burden for those already disabled by intractable pain or treatment resistant depression.

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PUBLIC WARNING

warning reprinted with permission of Demitri Papolos, MD
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Ketamine is a controlled substance.
Administered improperly, or without the guidance of a qualified doctor,
Ketamine may cause injury or death.
No attempt should be made to use Ketamine
in the absence of counsel from a qualified doctor.

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The material on this site is for informational purposes only.
.
It is not legal for me to provide medical advice without an examination.

.
It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

~~
This site is not for email and not for appointments.

If you wish an appointment, please telephone the office to schedule.

~~~~~

For My Home Page, click here:  Welcome to my Weblog on Pain Management!

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Please ignore the ads below. They are not from me.

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