Pain
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The placebo effect is considered the core example of mind-body interactions. However, individual differences produce large placebo response variability in both healthy volunteers and patients. The placebo response in pain, placebo analgesia, may be dependent on both the opioid system and the dopaminergic system. ⋯ Participants with OPRM1 Asn/Asn combined with COMT Met/Met and Val/Met reported significant pain relief after placebo administration, whereas those with other combinations of the OPRM1 and COMT genotypes displayed no significant placebo effect. Neither OPRM1 nor COMT had any significant influence on affective changes after placebo administration. As shown in this study, genotyping with regard to OPRM1 and COMT may predict who will respond favorably to placebo analgesic treatment.
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Interindividual differences in pain sensitivity vary as a function of interactions between sensory, cognitive-affective, and dispositional factors. Trait mindfulness, characterized as the innate capacity to nonreactively sustain attention to the present moment, is a psychological construct that is associated with lower clinical pain outcomes. Yet, the neural mechanisms supporting dispositional mindfulness are unknown. ⋯ Whole brain analyses revealed that higher dispositional mindfulness was associated with greater deactivation of a brain region extending from the precuneus to posterior cingulate cortex during noxious heat. These novel findings demonstrate that mindful individuals feel less pain and evoke greater deactivation of brain regions supporting the engagement sensory, cognitive, and affective appraisals. We propose that mindfulness and the posterior cingulate cortex should be considered as important mechanistic targets for pain therapies.
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Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. ⋯ The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor-mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.
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Interstitial cystitis/bladder pain syndrome (IC/BPS) is a prevalent, chronic bladder disorder that negatively impacts the quality of life for ∼5% of the western population. Hypersensitivity of mechanosensory afferents embedded within the bladder wall is considered a key component in mediating IC/BPS symptoms. Bladder infusion of voltage-gated sodium (Nav) channel blockers show clinical efficacy in treating IC/BPS symptoms; however, the current repertoire of Nav channels expressed by and contributing to bladder afferent function is unknown. ⋯ In vivo intrabladder infusion of TTX significantly reduces activation of dorsal horn neurons within the spinal cord to bladder distension. These data provide the first comprehensive analysis of Nav channel expression within sensory afferents innervating the bladder. They also demonstrate an essential role for TTX-S Nav channel regulation of bladder-innervating DRG neuroexcitability, bladder afferent responses to distension, and nociceptive signalling to the spinal cord.
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Peripheral neuropathy is the major dose-limiting side effect of many currently used chemotherapies, such as vincristine (VCR). We recently demonstrated that candesartan, an angiotensin II type 1 receptor antagonist, was neuroprotective against resiniferatoxin-induced sensory neuropathy, and that this effect is mediated by stimulation of the angiotensin II type 2 receptor (AT2R). Thus, we evaluated the effect of preventive treatment with candesartan and a specific AT2R agonist, C21, on a mouse model of VCR-induced neuropathy. ⋯ Both drugs prevented VCR-induced nonpeptidergic intraepidermal nerve fiber loss. Only C21 displayed neuroprotective effects against VCR-induced loss and enlargement of myelinated nerve fibers in the sciatic nerve. Our finding that candesartan and C21 are protective against VCR-induced neuropathic pain through AT2R stimulation favors evaluation of its therapeutic potential in patients receiving chemotherapy.