The journal of pain : official journal of the American Pain Society
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Neuropathic pain in rodents can be driven by ectopic spontaneous activity (SA) generated by sensory neurons in dorsal root ganglia (DRG). The recent demonstration that SA in dissociated human DRG neurons is associated with reported neuropathic pain in patients enables a detailed comparison of pain-linked electrophysiological alterations driving SA in human DRG neurons to alterations that distinguish SA in nociceptors from SA in low-threshold mechanoreceptors (LTMRs) in rodent neuropathy models. Analysis of recordings from dissociated somata of patient-derived DRG neurons showed that SA and corresponding pain in both sexes were significantly associated with the three functional electrophysiological alterations sufficient to generate SA in the absence of extrinsic depolarizing inputs. ⋯ These findings suggest that conserved physiological mechanisms of SA in human nociceptor somata can drive neuropathic pain despite documented cellular differences between human and rodent DRG neurons. PERSPECTIVE: Electrophysiological alterations in human sensory neurons associated with patient-reported neuropathic pain include all three of the functional alterations that logically can promote spontaneous activity. The similarity of distinctively altered spontaneous depolarizations in human DRG neurons and rodent nociceptors suggests that spontaneously active human nociceptors can persistently promote neuropathic pain in patients.
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The lateral parabrachial nucleus (LPBN) plays an important role in the processing and establishment of pain aversion. It receives direct input from the superficial dorsal horn and forms reciprocal connections with the periaqueductal grey matter (PAG), which is critical for adaptive behaviour and the modulation of pain processing. Here, using in situ hybridization and optogenetics combined with in vitro electrophysiology, we characterized the spinal- and PAG-LPBN circuits of rats. ⋯ These findings may support the efforts to develop pinpointed therapies for pain patients. PERSPECTIVE: The LPBN is an important brain region for the control of pain aversion versus recuperation, and as such constitutes a promising target for developing new strategies for pain management. We show that clinically-relevant drugs have complex and pathway-specific effects on LPBN processing of putative nociceptive and aversive inputs.
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Classic trigeminal neuralgia (CTN) is a neuropathic pain disorder displaying spontaneously stabbing or electric shock-like paroxysms in the face. Previous research suggests structural and functional abnormalities in brain regions related to sensory and cognitive-affective dimensions of pain contribute to the pathophysiology of CTN. However, few studies to date have investigated how changes in whole-brain functional networks and white matter connectivity are related to CTN. ⋯ These results suggest that altered structural and functional connectivity between aIns and ACC may underpin the aberrant SN in patients with CTN and provide an alternative target for clinical interventions. PERSPECTIVE: This article presents distinctive abnormalities of functional and structural connectivity from aIns to ACC in the patients with CTN, which is associated with pain ratings. This measure could potentially provide an alternative target for clinicians to alleviate this type of intermittent and refractory pain.
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Pain-related avoidance of movements that are actually safe (ie, overprotective behavior) plays a key role in chronic pain disability. Avoidance is reinforced through operant learning: after learning that a certain movement elicits pain, movements that prevent pain are more likely to be performed. Proprioceptive accuracy importantly contributes to motor learning and memory. ⋯ Furthermore, exploratory analyses indicated a reduction in proprioceptive accuracy after avoidance learning, which was associated with excessive avoidance and higher trait fear of pain. PERSPECTIVE: This study is the first to show that poorer proprioceptive accuracy is associated with excessive pain-related avoidance. This finding is especially relevant for chronic pain conditions, as reduced accuracy has been documented in these populations, and points toward the need for research on training accuracy to tackle excessive avoidance.
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Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. ⋯ Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PERSPECTIVE: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus.