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To determine whether pain-related treatment outcomes, following an online Cognitive Behavioural Therapy (CBT) intervention for chronic pain, were moderated by the pain etiology of a medically explained or unexplained origin.
Learn More >Voltage-dependent sodium (Na) 1.8 channels regulate action potential generation in nociceptive neurons, identifying them as putative analgesic targets. Here, we show that Na1.8 channel plasma membrane localization, retention, and stability occur through a direct interaction with the postsynaptic density-95/discs large/zonula occludens-1-and WW domain-containing scaffold protein called membrane-associated guanylate kinase with inverted orientation (Magi)-1. The neurophysiological roles of Magi-1 are largely unknown, but we found that dorsal root ganglion (DRG)-specific knockdown of Magi-1 attenuated thermal nociception and acute inflammatory pain and produced deficits in Na1.8 protein expression. A competing cell-penetrating peptide mimetic derived from the Na1.8 WW binding motif decreased sodium currents, reduced Na1.8 protein expression, and produced hypoexcitability. Remarkably, a phosphorylated variant of the very same peptide caused an opposing increase in Na1.8 surface expression and repetitive firing. Likewise, in vivo, the peptides produced diverging effects on nocifensive behavior. Additionally, we found that Magi-1 bound to sequence like a calcium-activated potassium channel sodium-activated (Slack) potassium channels, demonstrating macrocomplexing with Na1.8 channels. Taken together, these findings emphasize Magi-1 as an essential scaffold for ion transport in DRG neurons and a central player in pain.-Pryce, K. D., Powell, R., Agwa, D., Evely, K. M., Sheehan, G. D., Nip, A., Tomasello, D. L., Gururaj, S., Bhattacharjee, A. Magi-1 scaffolds Na1.8 and Slack K channels in dorsal root ganglion neurons regulating excitability and pain.
Learn More >Although complex regional pain syndrome (CRPS) of the knee is comparable to CRPS of the ankle/foot at time of diagnosis, no reports are available concerning the course of knee CRPS. Therefore, this study investigated the clinical course in terms of the symptoms and signs, health-related quality of life (HR-QoL), and work status of patients diagnosed with CRPS of the knee.
Learn More >Medication-overuse headache leads to high disability and decreased quality of life, and the best approach for withdrawal has been debated.
Learn More >Rheumatoid arthritis (RA) is an example of human chronic inflammatory pain. Modern treatments suppress inflammation, yet pain remains a major problem for many people with RA. We hypothesised that discrete RA subgroups might display favourable or unfavourable pain trajectories when receiving treatment, and that baseline characteristics will predict trajectory allocation. Growth Mixture Modelling was used to identify discrete trajectories of SF36-Bodily Pain scores during 3 years in 3 RA cohorts (Early RA Network (ERAN); n=683, British Society for Rheumatology Biologics Register Biologics (n=7090) and Non-Biologics (n=1720) cohorts. Logistic regression compared baseline predictor variables between trajectories. The role of inflammation was examined in a subgroup analysis of people with normal levels of inflammatory markers after 3 years. Mean SF36-Bodily Pain scores in each cohort improved but remained throughout 3y follow up >1 SD worse than the UK general population average. Discrete Persistent Pain (59% to 79% of cohort participants) and Resolving Pain (19% to 27%) trajectories were identified in each cohort. In ERAN, a third trajectory displaying persistently Low Pain (23%) was also identified. In people with normal levels of inflammatory markers after 3 years, 65% of them were found to follow a Persistent Pain trajectory. When trajectories were compared, greater disability (aORs 2.3-2.5 per unit baseline Health Assessment Questionnaire score) and smoking history (aORs 1.6-1.8) were risk factors for Persistent Pain trajectories in each cohort. In conclusion, distinct trajectories indicate patient subgroups with very different pain prognosis during RA treatment. Inflammation does not fully explain the pain trajectories, and non-inflammatory factors as well as acute phase response predict which trajectory an individual will follow. Targeted treatments additional to those which suppress inflammation might reduce the long term burden of arthritis pain. PERSPECTIVE: Immunosuppression reduces inflammation in RA, but pain outcomes are less favourable. Discrete Persistent and Resolving Pain trajectories were identified following treatment, both in early and established RA. Smoking and higher disability at baseline predicted persistent pain. Identifying patient subgroups with poor pain prognosis could enable adjunctive treatment to improve outcome.
Learn More >Dysregulated excitability within the spinal dorsal horn is a critical mediator of chronic pain. In the rodent nerve injury model of neuropathic pain, BDNF-mediated loss of inhibition (disinhibition) gates the potentiation of excitatory GluN2B N-methyl-d-aspartate receptor (NMDAR) responses at lamina I dorsal horn synapses. However, the centrality of this mechanism across pain states and species, as well as the molecular linker involved, remain unknown. Here, we show that KCC2-dependent disinhibition is coupled to increased GluN2B-mediated synaptic NMDAR responses in a rodent model of inflammatory pain, with an associated downregulation of the tyrosine phosphatase STEP61. The decreased activity of STEP61 is both necessary and sufficient to prime subsequent phosphorylation and potentiation of GluN2B NMDAR by BDNF at lamina I synapses. Blocking disinhibition reversed the downregulation of STEP61 as well as inflammation-mediated behavioural hypersensitivity. For the first time, we characterize GluN2B-mediated NMDAR responses at human lamina I synapses and show that a human ex vivo BDNF model of pathological pain processing downregulates KCC2 and STEP61 and upregulates phosphorylated GluN2B at dorsal horn synapses. Our results demonstrate that STEP61 is the molecular brake that is lost following KCC2-dependent disinhibition and that the decrease in STEP61 activity drives the potentiation of excitatory GluN2B NMDAR responses in rodent and human models of pathological pain. The ex vivo human BDNF model may thus form a translational bridge between rodents and humans for identification and validation of novel molecular pain targets.
Learn More >Prevalence of migraine is high during the reproductive age. Although migraine often improves during pregnancy, the risk of adverse pregnancy, birth, neonatal, and neurological outcomes in mother and offspring remains poorly understood.
Learn More >Migraine is a strongly disabling disease characterized by a unilateral throbbing headache lasting for up to 72 h for each individual attack. There have been many theories on the pathophysiology of migraine throughout the years. Currently, the neurovascular theory dominates, suggesting clear involvement of the trigeminovascular system. The most recent data show that a migraine attack most likely originates in the hypothalamus and activates the trigeminal nucleus caudalis (TNC). Although the mechanisms are unknown, activation of the TNC leads to peripheral release of calcitonin gene-related protein (CGRP), most likely from C-fibers. During the past year monoclonal antibodies against CGRP or the CGRP receptor have emerged as the most promising targets for migraine therapy, and at the same time established the strong involvement of CGRP in the pathophysiology of migraine. The viewpoint presented here focuses further on the activation of the CGRP receptor on the sensory Aδ-fiber, leading to the sensation of pain. The CGRP receptor activates adenylate cyclase, which leads to an increase in cyclic adenosine monophosphate (cAMP). We hypothesize that cAMP activates the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, triggering an action potential sensed as pain. The mechanisms behind migraine pain on a molecular level, particularly their importance to cAMP, provide clues to potential new anti-migraine targets. In this article we focus on the development of targets related to the CGRP system, and further include novel targets such as the pituitary adenylate cyclase-activating peptide (PACAP) system, the serotonin 5-HT receptor, purinergic receptors, HCN channels, adenosine triphosphate-sensitive potassium channels (K), and the glutaminergic system.
Learn More >Because the results of clinical trials of investigational treatments influence regulatory policy, prescribing patterns, and use in clinical practice, high quality trials are an essential component of the evidence base for migraine. The International Headache Society has published guidelines for clinical trials in adults with migraine since 1991. With multiple issues specific to children and adolescents with migraine, as well as the emergence of novel trial designs and advances in pharmaceuticals, biologics, devices, and behavioural interventions, there is a need for guidance focusing on issues specific to the conduct of clinical trials in children and adolescents with migraine.
Learn More >Migraine is a disabling primary headache disorder that requires effective treatments. Inhalation is currently being explored for the delivery of drugs for migraine. Pulmonary-route delivery of drugs shows potential advantages for its use as a treatment, particularly compared the oral route. Areas covered: The authors highlight the current state of the literature and review multiple therapies for migraine-utilizing inhalation as the route of administration. The following therapeutics are discussed: inhaled ergotamine, inhaled dihydroergotamine mesylate (MAP0004), inhaled prochlorperazine, and inhaled loxapine. Coverage is also given to normobaric oxygen, hyperbaric oxygen, and nitrous oxide therapies. Expert opinion: Inhalation of MAP0004 showed promising results in terms of efficacy for acute migraine treatment in phase 3 studies, together with a more favorable tolerability profile compared to parenteral dosing and a better pharmacokinetic profile versus oral or intranasal delivery. In phase 2 trials, inhaled prochlorperazine shows good pharmacokinetics and efficacy, in contrast to inhaled loxapine that did not provide encouraging results in terms of efficacy. The authors see the potential for the use of dihydroergotamine mesylate in clinical practice pending regulatory approval.
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