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Specific components of physical activity, such as vigorous exercise and heavy occupational work, are known to increase the risk of chronic low back pain (CLBP) and knee pain (CKP), but impacts of other components are less known. This study aimed to assess the relationship between total physical activity and risk of CLBP and CKP from a public health perspective.
Learn More >Animal studies have suggested that transient receptor potential (TRP) ion channels and G protein-coupled receptors (GPCRs) play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis (AD), whereas their inhibition attenuated scratching and inflammatory responses in mouse AD models. Taken together, these results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in AD.
Learn More >Drugs selectively targeting CB2 hold promise for treating neurodegenerative disorders, inflammation, and pain while avoiding psychotropic side effects mediated by CB1. The mechanisms underlying CB2 activation and signaling are poorly understood but critical for drug design. Here we report the cryo-EM structure of the human CB2-G signaling complex bound to the agonist WIN 55,212-2. The 3D structure reveals the binding mode of WIN 55,212-2 and structural determinants for distinguishing CB2 agonists from antagonists, which are supported by a pair of rationally designed agonist and antagonist. Further structural analyses with computational docking results uncover the differences between CB2 and CB1 in receptor activation, ligand recognition, and G coupling. These findings are expected to facilitate rational structure-based discovery of drugs targeting the cannabinoid system.
Learn More >Non-invasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton Magnetic Resonance Spectroscopy (H-MRS) metabolites have been linked with glial activity (i.e. choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting fMRI connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (p=0.03), with greater choline levels linked with worse pain interference (r=0.41, p=0.01). In addition, reduced resting functional connectivity between anterior insula and putamen was associated with both pain interference (whole brain analysis, pcorrected<0.01) and elevated anterior insula choline (r=-0.37, p=0.03). In fact, anterior insula/putamen connectivity statistically mediated the link between anterior insula choline and pain interference (p<0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. In order to further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex-vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r=0.49, p=0.03). Choline, a putative neuroinflammatory H-MRS assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.
Learn More >To investigate and compare the safety and the pharmacokinetics of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), intranasal DHE spray (Migranal ), and intramuscular (IM) DHE injection in healthy subjects.
Learn More >Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder typically in the upper or lower limbs. Whilst CRPS usually develops from a peripheral event, it is likely maintained by central nervous system changes. Indeed CRPS is reported to be associated with sensorimotor cortex changes, or functional 'reorganisation', as well as deficits such as poor tactile acuity. Whilst the mechanisms underpinning cortical reorganisation in CRPS are unknown, some have hypothesised that it involves disinhibition, i.e. a reduction in gamma-Aminobutyric acid (GABA) activity. In this study we addressed this hypothesis by using edited magnetic resonance spectroscopy (MRS) to determine sensorimotor GABA and glutamate concentrations in 16 humans with CRPS and 30 matched controls and the relationship of these concentrations with tactile acuity. We found that individuals with upper limb CRPS displayed reduced tactile acuity in the painful hand compared with the non-painful hand and pain-free controls. Despite this acuity deficit, CRPS was not associated with altered GABA or glutamate concentrations within the sensorimotor cortex on either the side that represents the affected or unaffected hand. Furthermore, there was no significant relationship between sensorimotor GABA or glutamate concentrations and tactile acuity in CRPS or control subjects. Although our sample was small, these data suggest that CRPS is not associated with altered total sensorimotor GABA or glutamate concentrations. Whilst these results are at odds with the sensorimotor cortex disinhibition hypothesis, it is possible that GABAergic mechanisms other than total GABA concentration may contribute to such disinhibition. Complex regional pain syndrome is a debilitating chronic pain disorder that usually affects the limbs. It is associated with altered sensorimotor cortex function including reorganisation and reduced tactile acuity, which are thought to result from reduced on-going inhibition. However, we found that this pain condition is not associated with reduced on-going sensorimotor inhibition in the form of gamma-Aminobutyric acid concentration, the major inhibitory neurotransmitter in the brain. These findings strongly suggest that changes in sensorimotor function in individuals with complex regional pain syndrome are explained by factors other than neurotransmitter concentration.
Learn More >Severe pre- and acute postoperative pain have been associated with development of chronic postoperative pain. Chlorzoxazone (a muscle relaxant) has been suggested to enhance acute postoperative pain recovery but the lack of larger randomized controlled trials have however questioned the continued use. Despite this, chlorzoxazone is still used for acute postoperative pain management following total knee or hip replacement (TKR or THR). The currentrandomized, double blinded, placebo-controlled, parallel group, clinical trial aimed to assess the effect of chlorzoxazone for postoperative pain management following TKR or THR.
Learn More >Developing effective analgesics with fewer unwanted side effects is a pressing concern. Due to a lack of effective nonopioid options currently available, an alternative approach termed opioid-sparing evaluates the ability of a coadministered drug to reduce the amount of opioid needed to produce an antinociceptive effect. Opioids and benzodiazepines are often coprescribed. Although this approach is theoretically rational given the prevalent comorbidity of chronic pain and anxiety, it also has inherent risks of respiratory depression, which is likely responsible for the substantial percentage of fatal opioid overdoses that have involved benzodiazepines. Moreover, there have been no clinical trials to support the effectiveness of this drug combination nor has there been corroborative preclinical evidence using traditional animal models of nociception. The present studies examined the prescription µ-opioid analgesic oxycodone (0.003-0.1 mg/kg) and the prototypical benzodiazepine anxiolytic diazepam (0.03-1.0 mg/kg), alone and in combination, using an animal model of pain that examines the restoration of conflict-related operant behavior as evidence of analgesia. Results documented significant dose-related increases in thermal threshold following oxycodone treatment. Diazepam treatment alone did not produce significant antinociception. In combination, diazepam pretreatment shifted oxycodone functions upward in a dose-dependent manner, but the additive effects were limited to a narrow dose range. In addition, combinations of diazepam and oxycodone at higher doses abolished responding. Taken together, though intriguing, these findings do not provide sufficient evidence that coadministration of an anxiolytic will result in clinically relevant opioid-sparing for pain management, especially when considering the inherent risks of this drug class combination.
Learn More >EpiFibro (Brazilian Epidemiological Study of Fibromyalgia) was created to study patients with fibromyalgia (FM). Patients were included since 2011 according to the classification criteria for FM of the American College of Rheumatology of 1990 (ACR1990).
Learn More >Nausea and vomiting are often associated with opioid analgesia in cancer patients; however, only a subset of patients develop such side effects. Here, we tested the hypothesis that the occurrence of nausea and vomiting is modulated by the genetic background of the patients. Whole exome sequencing of DNA pools from patients with either low (n = 937) or high (n = 557) nausea and vomiting intensity, recruited in the European Pharmacogenetic Opioid Study, revealed a preliminary association of 53 polymorphisms. PCR-based genotyping of 45 of these polymorphisms in the individual patients of the same series confirmed the association for six SNPs in AIM1L, CLCC1, MUC16, PDE3A, POM121L2, and ZNF165 genes. Genotyping of the same 45 polymorphisms in 264 patients of the Italian CERP study, also treated with opioids for cancer pain, instead confirmed the association for two SNPs in ZNF568 and PDE3A genes. Only one SNP, rs12305038 in PDE3A, was confirmed in both series, although with opposite effects of the minor allele on the investigated phenotype. Overall, our findings suggest that genetic factors are indeed associated with nausea and vomiting in opioid-treated cancer patients, but the role of individual polymorphisms may be weak.
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