Recent research published in Nature Neuroscience reports on the discovery of ‘a multidomain scaffolding protein‘ that binds several elements together in a specific system. This complex system is responsible for regulating chronic pain and fragile X syndrome, among other neurologic problems.
The researchers looked at group 1 metabotropic glutamate receptors (mGluRs); including mGluR1 and mGluR5, both “G-protein-coupled receptors that are expressed at excitatory synapses in brain and spinal cord.”
In order for responses such as pain to cease after they are no longer required, these receptors need to be turned off thus preventing neurons from being continuously active. In the past scientists have found that mGluRs could possibly require binding to an adaptor protein named Homer in order to switch off, and stronger binding is facilitated by phosphorylation of the binding site by proline-directed kinases.
How this mechanism occurs was previously unknown and the investigators of this study conducted experiments using rat brains to determine which proteins were binding to mGluRs and Homer. The results of the study demonstrated that the mechanism is “dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site.”
In order to determine the exact role of Preso1 the scientists examined neurons that produced mGluRs and Homer, and discovered that more efficient binding of mGluRs and Homer occurred when these neurons coexpressed Preso1. This finding could mean that Preso1 may play a part in increasing the modification by protein kinases. Indeed, researchers found that Preso1 also binds to protein kinases.
In genetically modified mice that do not make Preso1, binding of mGluRs with Homer in their neurons was less, in comparison to normal mice. Furthermore, upon injection of the genetically modified mice with a pain- and inflammation-causing chemical, there was a “significantly greater and longer-lasting response” in comparison with normal mice.
Investigators also demonstrated that neurons taken from the genetically modified mice were more responsive to glutamate, and upon addition of Preso1 to the cell cultures, the increase in activity previously observed ceased. This suggests that Preso1 plays a ‘pivotal‘ role in the proper signaling of mGluRs.
According to the leader of the study, Paul Worley (Johns Hopkins University School of Medicine, MD, USA), all these study findings appear to show that Preso1 brings together all the parts of the system in order to “coordinate the activation and deactivation of the mGluRs.”
Worley states, “Because mGluRs play so many important roles in the brain for so many different mental and neurological health conditions, knowledge of their regulatory mechanisms is extremely important. But we really don‘t know how they work in great detail. You need to know all the players before you can understand the system. Here, we‘ve identified an important player that no one had previously known had existed. Preso1 and Homer appear essential for desensitization of mGluR signaling, much like beta-adrenergic receptor kinase and arrestin are important for desensitization of adrenergic and opiate receptors.”
Preso1 could provide a very useful and exciting new therapeutic target for several health conditions where group 1 mGluR receptors could be involved, including chronic pain. Further studies are required to determine if this is indeed the case.
– Written by Roshaine Gunawardana
Sources: Johns Hopkins Medicine – News and Publications: www.hopkinsmedicine.org/news/media/releases/newly_discovered_scaffold_supports_turning_pain_off; Hu JH, Yang L, Kammermeier PJ et al. Preso1 dynamically regulates group I metabotropic glutamate receptors. Nat. Neurosci. 15, 836–844 (2012).
Rheumatoid arthritis (RA) is a disease consisting of pain, swelling, inflammation and soreness of the joints. This systemic disease can cause the sufferer to become limited in their daily activities and in some instances causes permanent disability. RA has a worldwide prevalence of 1% and the disease is most common women between the ages of 20 and 40 years and those situated in developing countries.
Experts recommend premature intervention for the treatment of RA where inflammatory processes can be interfered with as early as possible. Daniel Aletaha (Medical University Vienna, Vienna, Austria) explained, “Discussion of treatment options by patients and physicians is important in the management of RA.” The ACR and European League Against Rheumatism have recently standardized the criteria for how the disease activity in RA is measured. Patients are currently asked to evaluate their condition via the patient global assessment (PGA). Rheumatologists measure the disease using the evaluator global assessment (EGA). Aletaha comments on the differing views this can cause, “Many times there is a discrepancy between patients‘ and doctors‘ views of disease activity, with doctors providing a better rating then patients.”
The study comprised of 646 RA patients from an observational patient database who had begun methotrexate therapy. Patients and physicians completed their respective PGA and EGA assessments. It was these assessments that were used by the research team to analyze their findings.
The results clarified how the variability in the assessments could be explained by the various measures in RA patients. Pain determines PGA variation by 76%, while for EGA assessments swollen joints attribute 61% to variability and just 5% by pain. Only 0.5% of PGA variability is down to swollen joints. Aletaha concludes on these findings, “Our study shows pain really drives patient perception of disease activity, while physicians mostly rely on the number of swollen joints when they interpret a patient‘s disease activity. The discrepancy of perception between patients and physicians were calculated as PGA minus EGA. Pain levels and joint swelling are again explaining these discrepancies to a great deal.”
Further understanding the reasons for the differing views on RA disease activity could potentially lead to better decision-making between patients and their physicians in handling RA.
– Written by Priti Nagda
Sources: Wiley Press Room, Press Releases: http://eu.wiley.com/WileyCDA/PressRelease/pressReleaseId-104131.html; Studenic P, Radner H, Smolen JS, Aletaha D. Discrepancies between patients and physicians in the perception of rheumatoid arthritis disease activity. Arthritis Rheum. doi:10.1002/art.34543 (2012).
Scientists have found that a ‘standard dose‘ of external beam radiation therapy leads to patients with plantar fasciiitis experiencing “significantly less pain and improved quality of life.” The study was published recently in the International Journal of Radiation Oncology, Biology, Physics.
According to the American Academy of Orthopedic Surgeons ‘OrthoInfo‘ webpage, plantar fasciitis is “the most common cause of pain on the bottom of the heel” and quotes approximately 2 million individuals per year as receiving treatment for this painful condition. The most common treatments for the pain reduction include certain anti-inflammatory agents, ice and heat. The individual could possibly be prescribed oral analgesics, or be administered steroid or local anesthetic injections. For the majority of these methods the pain relief is short term.
In the study, a total of sixty six patients were randomized to receive radiation therapy with either a dose of 6.0 Gy given in 6 fractions of 1.0 Gy twice weekly – the standard dose – or a total dose of 0.6 Gy given in 6 fractions of 0.1 Gy twice weekly – the low dose. The main part of the study was completed after 3 months and follow-up was carried out for a period of up to 1 year.
After 3 months results were “highly significantly superior” in the standard arm in comparison with the patients taking low-dose therapy. Up to 80% of standard-dose patients had complete pain relief and this relief actually stayed constant, or improved for up to 64% of patients in the study at 48 weeks after treatment (follow-up period). After 1-year follow-up, “highly significant fewer patients” in the standard-dose arm required reirradiation compared with those in the low-dose arm.
One study author, Marcus Niewald (Saarland University Medical Center, Homburg/Saar, Germany) explains, “Severe plantar fasciitis is a chronic health issue, and it can be extremely painful – many of these men and women cannot walk or stand for a long time. Radiation therapy has been used for its anti-inflammatory effect for more than 60 years. We are extremely encouraged by the results of our research because evidence of improved quality of life for patients is clearly evident with the standard-dose regimen.”
– Written by Roshaine Gunawardana
Sources: American Society for Radiation Oncology (ASTRO) News and Media Center: www.astro.org/News-and-Media/News-Releases/2012/Standard-radiation-therapy-dose-provides--relief-for-painful-heel-spurs.aspx; Niewald M, Seegenschmiedt MH, Micke O et al. Randomized, multicenter trial on the effect of radiation therapy on plantar fasciitis (painful heel spur) comparing a standard dose with a very low dose: mature results after 12 months‘ follow-up. Int. J. Radiat. Oncol. Biol. Phys. doi:10.1016/j.ijrobp.2012.06.022 (2012) (Epub ahead of print); American Academy of Orthopaedic Surgeons: http://orthoinfo.aaos.org/topic.cfm?topic=A00149
Researchers at Northwestern University (IL, USA) have discovered that morphological changes in brain structure could be responsible for pain chronification. Data from the study recently published in Nature Neuroscience seem to suggest that communication between the frontal cortex and the nucleus accumbens is key to the development of chronic pain. Understanding this connection could lead to new treatments aimed at preventing chronic pain from ever developing.
Corticostriatal communication connects the emotional centers of the brain to those responsible for processing pain; consequently, pain is more likely to persist after the injury has healed in brains that respond to pain more emotionally. The level of excitability and communication between the frontal cortex and the nucleus accumbens varies greatly between individuals, and is determined by a number of factors including genetic predisposition and environmental influences.
“For the first time we can explain why people who may have the exact same initial pain either go on to recover or develop chronic pain,” states Vania Apakarian, senior author of the paper and Professor of Physiology, Surgery, Anesthesia, Cognitive Brain Mapping Group, and Neuroscience Institute at Northwestern University. “The injury by itself is not enough to explain the ongoing pain. It has to do with the injury combined with the state of the brain.”
The 1-year study recruited 40 participants who were suffering from subacute back pain lasting between 4 and 16 weeks. The participants‘ corticostriatal circuitry was assessed using fMRI scans at the start of the study, followed by three additional scans over the course of the year. Researchers were able to predict with 85% accuracy which of the participants would develop chronic pain, based on their theories about communication between the frontal cortex and the nucleus accumbens, following the initial scans.
Patients who went on to develop pain persistence demonstrated an initial increase in corticostriatal connectivity, followed by a final decrease in gray matter density compared with recovering participants and healthy controls. This implies that the corticostriatal connectivity studied plays a causative role in the development of chronic pain.
This study has opened a new avenue for drug development for the prevention rather than the treatment of chronic pain. Apkarian added, “Chronic pain is one of the most expensive healthcare conditions in the US yet there still is not a scientifically validated therapy for this condition. Now we hope to develop new therapies for treatment based on this finding.”
– Written by Sophie Breeze
Sources: Baliki MN, Petre B, Torbey S et al. Corticostriatal functional connectivity predicts transition to chronic back pain. Nat. Neurosci. 15, 1117–1119 (2012); Why Chronic Pain is All in Your Head: www.northwestern.edu/newscenter/stories/2012/07/chronic-pain-apkarian.html
A new Risk Evaluation and Mitigation Strategy (REMS) has recently been approved by the US FDA to tackle the misuse of long-acting (LA) and extended-release (ER) opioids in response to fears of drug abuse. It is hoped that new safety measures will lower the risks associated with opioid use, and ensure that patients suffering from persistent pain can access and use LA and ER opioids safely.
“Misuse and abuse of prescription opioids is a complex problem and demands a holistic response,” says John Jenkins, director of Center for Drug Evaluation and Research Office of New Drugs (MD, USA). “The new REMS program is one component of a multiagency, national strategy to address this important public health issue.”
The incidence of death by overdose of ER/LA opioids has been on the rise for the last 10 years. The CDC report that ER/LA opioid analgesics were responsible for 15,597 deaths in the USA in 2009, a total number of deaths four-times higher than 1999 figures. The new REMS initiative aims to curb the overdose ‘epidemic‘ escalating in the future and ensure that the benefits of ER/LA opioids continue to outweigh the risks.
“Misprescribing, misuse and abuse of ER and LA opioids are a critical and growing public health challenge,” says FDA Commissioner Margaret A Hamburg. “The FDA‘s goal with this REMS approval is to ensure that healthcare professionals are educated on how to safely prescribe opioids and that patients know how to safely use these drugs.”
Training of health professionals who prescribe ER/LA analgesics will be crucial to the success of REMS. Improved assessment guidelines will help heath professions make decisions regarding suitable candidates for initiation of treatment, followed by guidance on dosing, monitoring and counseling regimes. Emphasis will also be placed on additional training for prescribers to recognize evidence of and the potential for opioid misuse, abuse and addiction.
Patient counseling about individual responsibility of patients to use their medication safely will be provided along with a new Medication Guide, giving advice on the storage, use and disposal of ER/LA opioids. The guide will also advise patients how to recognize signs of potential overdose, and give contact instructions in case of an emergency.
The education of ER/LA opioid prescribers is due to commence in March 2013.
– Written by Sophie Breeze
Sources: US FDA news releases: www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm; www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm310870.htm