Pain
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Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). ⋯ Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.
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Randomized Controlled Trial
A randomized, double-blind, placebo-controlled trial of ISC 17536, an oral inhibitor of TRPA1, in patients with painful diabetic peripheral neuropathy: impact of preserved small nerve fiber function.
Patients with chronic pain syndromes, such as those with painful peripheral neuropathy due to diabetes mellitus, have limited treatment options and suffer ongoing attrition of their quality of life. Safer and more effective treatment options are needed. One therapeutic approach encompasses phenotypic characterization of the neuropathic pain subtype, combined with the selection of agents that act on relevant mechanisms. ⋯ However, statistically significant and clinically meaningful improvement in pain were seen with ISC 17536 in an exploratory hypothesis-generating subpopulation of patients with preserved small nerve fiber function defined by quantitative sensory testing. These results may provide a mechanistic basis for targeted therapy in specific pain phenotypes in line with current approaches of "precision medicine" or personalized pain therapeutics. The hypothesis is planned to be tested in a larger phase 2 study.
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A number of studies have demonstrated substantial individual differences in placebo effects. We aimed to identify individual psychological factors that potentially predicted the magnitude of placebo hypoalgesia and individual responsiveness. The Research Domain Criteria framework and a classical conditioning with suggestions paradigm were adopted as experimental models to study placebo phenotypes in a cohort of 397 chronic pain participants with a primary diagnosis of temporomandibular disorder (TMD) and 397 healthy control (HC) participants. ⋯ A greater level of emotional distress was a significant predictor of smaller magnitude (slope b = -0.07) and slower extinction rate (slope b = 0.51) of placebo effects in both TMD and HC participants. Greater reward seeking was linked to greater postconditioning expectations (ie, reinforced expectations) in TMD (slope b = 0.16), but there was no such a prediction in HC participants. These findings highlight that negative valence systems might play a role in impairing placebo effects, with a larger impact in chronic pain participants than in healthy participants, suggesting that individuals reporting emotional distress and maladaptive cognitive appraisals of pain may benefit less from placebo effects.
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Increased sensory sensitivity across non-nociceptive modalities is a common symptom of chronic pain conditions and is associated with chronic pain development. Providing a better understanding of the brain-behavior relationships that underlie multimodal hypersensitivity (MMH) may clarify the role of MMH in the development of chronic pain. We studied sensory hypersensitivity in a cohort of women (n = 147) who had diary confirmation of menstrual status and were enriched with risk factors for chronic pelvic pain, such as dysmenorrhea and increased bladder sensitivity. ⋯ These results demonstrate that activity in the primary visual cortex is not greater in individuals with greater visceral sensitivity. We hypothesize that downstream interpretation or integration of this signal is amplified in individuals with visceral hypersensitivity. Future studies aimed at reducing MMH in chronic pain conditions should prioritize targeting of cortical mechanisms responsible for aberrant downstream sensory integration.
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The innate motivation to avoid pain can be disrupted when individuals experience uncontrollable stress, such as pain. This can lead to maladaptive behaviors, including passivity, and negative affect. Despite its importance, motivational aspects of pain avoidance are understudied in humans and their neural mechanisms vastly unknown. ⋯ Higher helplessness in participants with migraine was further correlated with a stronger decrease in activation of cortical areas associated with motor behavior, attention, and memory after unsuccessful pain avoidance. Of these areas, specifically posterior parietal cortex activation predicted individual's pain avoidance behavior on the next trial. The results link individual pain coping capacity to patterns of neural activation associated with altered pain avoidance in patients with migraine.