Pain
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Central poststroke pain (CPSP) is a debilitating and often treatment-refractory condition that affects numerous stroke patients. The location of lesions most likely to cause pain and the identity of the functional brain networks that they impinge upon remain incompletely understood. We aimed to (1) elucidate which lesion locations are most frequently accompanied by pain; (2) explore CPSP-associated functional networks; and (3) examine how neuromodulation interacts with these networks. ⋯ The extent of connectivity to the thalamus, inferior parietal lobule, and precuneus also differed between CPSP and control lesions (PBonferroni < 0.05). Posterior insula and thalamus shared connectivity with both CPSP lesions and pain-alleviating DBS activation volumes (PBonferroni < 0.05). These findings further clarify the topography and functional connectivity of pain-causing brain lesions, and provide new insights into the network-level mechanism of CPSP neuromodulation.
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Chronic posttraumatic headache (PTH) is among the most common and disabling sequelae of traumatic brain injury (TBI). Current PTH treatments are often only partially effective and have problematic side effects. We previously showed in a small randomized trial of patients with chronic nontraumatic headaches that manipulation of dietary fatty acids decreased headache frequency, severity, and pain medication use. ⋯ Statistical analyses assessed the association of oxylipins with headache severity (primary outcome, measured by headache question on NSI) as well as associations between oxylipins and total NSI or satisfaction with life survey scores. Among oxylipins, 4-hydroxy-DHA and 19,20-epoxy-docosapentaenoate (DHA derivatives) were inversely associated with headache severity, and 11-hydroxy-9-epoxy-octadecenoate (a linoleic acid derivative) was positively associated with headache severity. These findings support a potential for DHA-derived oxylipins as prognostic biomarkers for development of chronic PTH.
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Offset analgesia identifies impaired endogenous pain modulation in pediatric chronic pain disorders.
Offset analgesia (OA), a psychophysical test of endogenous pain inhibition, is diminished in many adult chronic pain disorders but OA has not been investigated in youth with chronic pain disorders. This study assessed OA responses in 30 youth with chronic primary and secondary pain disorders and 32 healthy controls. The OA, control, and constant thermal tests were evoked with an individualized noxious heat stimulus of approximately 50/100 mm on a visual analogue scale followed by 1°C offset temperature. ⋯ Central Sensitization Inventory scores showed excellent predictive accuracy in differentiating patients from controls (area under the curve = 0.95; 95% CI: 0.91-0.99) and CSI score ≥30 was identified as an optimal cutoff value. Pain Sensitivity Questionnaire scores did not differentiate patients from controls nor correlate with OA. In this study, 60% of youth with chronic pain showed reduced capacity for endogenous pain inhibition.
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Currently, opioids targeting mu-opioid receptors are the most potent drugs for acute and cancer pain. However, opioids produce adverse side effects such as constipation, respiratory depression, or addiction potential. We recently developed (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a compound that does not evoke central or intestinal side effects due to its selective activation of mu-opioid receptors at low pH in peripheral injured tissues. ⋯ We demonstrate that low, but not higher, doses of NFEPP produce conditioned place preference but not constipation or motor disturbance, in contrast to fentanyl. Using a peripherally restricted antagonist, we provide evidence that NFEPP-induced place preference is mediated by peripheral opioid receptors. Our results indicate that a low dose of NFEPP produces reward by abolishing spontaneous inflammatory pain.
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Luminal distension and abdominal pain are major clinical hallmarks of obstructive bowel disorders and functional bowel disorders linked to gut dysbiosis. Our recent studies found that chronic lumen distension increased visceral sensitivity and decreased abundance of gut commensal Lactobacillus reuteri in a rodent model of partial colon obstruction (OB). To establish causation, we performed precision microbial therapy to assess whether recolonization of L. reuteri prevents visceral hypersensitivity in lumen distension, and if so, to identify the gut-microbiota mechanism. ⋯ However, L. reuteri treatment prevented the loss of opioid receptors. Furthermore, administration of peripheral opioid receptor antagonist naloxone methiodide abolished the analgesic effect of L. reuteri in OB. In conclusion, precision L. reuteri therapy prevents lumen distension-associated visceral hypersensitivity by local bacterial induction of opioid receptors.