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We examined the reliability and validity of the 6-item Headache Impact Test (HIT-6) specifically on patients with chronic migraine (CM) from the PROMISE-2 clinical trial.
Learn More >Understanding the activation mechanism of the μ-opioid receptor (μ-OR) and its selective coupling to the inhibitory G protein (G) is vital for pharmaceutical research aimed at finding treatments for the opioid overdose crisis. Many attempts have been made to understand the mechanism of the μ-OR activation, following the elucidation of new crystal structures such as the antagonist- and agonist-bound μ-OR. However, the focus has not been placed on the underlying energetics and specificity of the activation process. An energy-based picture would not only help to explain this coupling but also help to explore why other possible options are not common. For example, one would like to understand why μ-OR is more selective to G than a stimulatory G protein (G). Our study used homology modeling and a coarse-grained model to generate all of the possible "end states" of the thermodynamic cycle of the activation of μ-OR. The end points were further used to generate reasonable intermediate structures of the receptor and the G to calculate two-dimensional free energy landscapes. The results of the landscape calculations helped to propose a plausible sequence of conformational changes in the μ-OR and G system and for exploring the path that leads to its activation. Furthermore, in silico alanine scanning calculations of the last 21 residues of the C terminals of G and G were performed to shed light on the selective binding of G to μ-OR. Overall, the present work appears to demonstrate the potential of multiscale modeling in exploring the action of G protein-coupled receptors.
Learn More >Useful animal models of disease in neuroscience can make accurate predictions about a therapeutic outcome, a feature known as predictive validity. In this issue of the JCI, Knowland et al. provide an improved model to assess nicotinic acetylcholine receptor (nAChR) ligands for treating chronic pain. The authors identify two proteins, the voltage-dependent calcium channel auxiliary subunit BARP and the unfolded protein response sensor IRE1α, that are required for robust heterologous expression of α6β4, an nAChR subtype in dorsal root ganglia (DRG). This nAChR is a candidate for the analgesic effects of nicotine as well as the frog toxin epibatidine. Now researchers can efficiently screen for α6β4 nAChR-selective agonists using heterologous expression systems. Candidates that emerge will enable researchers to test the predictive validity of mouse models for chronic pain in the nAChR context. If all these steps work, one can envision a class of non-opioid nAChR-targeted analgesics for chronic pain.
Learn More >The α6β4 nicotinic acetylcholine receptor (nAChR) is enriched in dorsal root ganglia neurons and is an attractive non-opioid therapeutic target for pain. However, difficulty expressing human α6β4 receptors in recombinant systems has precluded drug discovery. Here, genome-wide screening identified accessory proteins that enable reconstitution of human α6β4 nAChRs. BARP, an auxiliary subunit of voltage-dependent calcium channels, promoted α6β4 surface expression while IRE1α, an unfolded protein response sensor, enhanced α6β4 receptor assembly. Effects on α6β4 involve BARP's N-terminal region and IRE1α's splicing of XBP1 mRNA. Furthermore, clinical efficacy of nicotinic agents in relieving neuropathic pain best correlated with their activity on α6β4. Finally, BARP-knockout, but not NACHO-knockout mice lacked nicotine-induced antiallodynia, highlighting the functional importance of α6β4 in pain. These results identify roles for IRE1α and BARP in neurotransmitter receptor assembly and unlock drug discovery for the previously elusive α6β4 receptor.
Learn More >The main objective of this study was to determine whether ()-3-furan-2-yl—tolyl-acrylamide (PAM-2) and its structural derivative DM489 produce anti-neuropathic pain activity using the streptozotocin (STZ)- and oxaliplatin-induced neuropathic pain animal models. To assess possible mechanisms of action, the pharmacological activity of these compounds was determined at α7 and α9α10 nicotinic acetylcholine receptors (nAChRs) and Ca2.2 channels expressed alone or coexpressed with G protein-coupled GABA receptors. The animal results indicated that a single dose of 3 mg/kg PAM-2 or DM489 decreases STZ-induced neuropathic pain in mice, and chemotherapy-induced neuropathic pain is decreased by PAM-2 (3 mg/kg) and DM489 (10 mg/kg). The observed anti-neuropathic pain activity was inhibited by the α7-selective antagonist methyllycaconitine. The coadministration of oxaliplatin with an inactive dose (1 mg/kg) of PAM-2 decreased the development of neuropathic pain after 14, but not 7, days of cotreatment. The electrophysiological results indicated that PAM-2 potentiates human (h) and rat (r) α7 nAChRs with 2-7 times higher potency than that for hCa2.2 channel inhibition and an even greater difference compared to that for rα9α10 nAChR inhibition. These results support the notion that α7 nAChR potentiation is likely the predominant molecular mechanism underlying the observed anti-nociceptive pain activity of these compounds.
Learn More >A randomized controlled trial compared cognitive behavioral therapy (CBT) and diabetes education (ED) as an adjunctive treatment for diabetic peripheral neuropathic pain (DPNP). We examined change from baseline to 12- and 36-week follow-up in overall pain intensity (NRS), neuropathic pain intensity/quality, pain interference, and mental health functioning, among others. Although CBT participants demonstrated improvement in pain intensity NRS, there were no between-condition differences at either follow-up. CBT reduced neuropathic pain intensity at 12-weeks more than ED. At 36-weeks, CBT was superior to ED for improving pain interference and mental health functioning. Results provide evidence of benefit of CBT for DPNP.: NCT00830011.
Learn More >Somatic symptoms capture attention, demand interpretation, and promote health behaviors. Symptom appraisal is particularly impactful within uncertain health contexts such as cancer survivorship. Yet, little is known about how individuals make sense of somatic symptoms within uncertain health contexts, nor how this process guides health behaviors.
Learn More >In a recent issue, Kovacic et al. analyze data from a randomized sham-controlled trial and show that pretreatment vagal efficiency, an index related to respiratory sinus arrhythmia, is a predictor of pain improvement in adolescents with functional abdominal pain when treated with auricular percutaneous electrical nerve field stimulation. The underlying premise is the polyvagal hypothesis, an explanatory framework for the evolution of the mammalian autonomic nervous system, which proposes that functional gastrointestinal disorders can result from a chronic maladaptive state of autonomic neural control mechanisms after traumatic stress. This is an opportunity for us to stimulate physicians' interest in evolutionary medicine.
Learn More >Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively.
Learn More >To assess the association between migraine and cryptogenic ischemic stroke (CIS) in young adults, with subgroup analyses stratified by sex and presence of patent foramen ovale (PFO).
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