Spinal cord homeostatic plasticity gates mechanical allodynia in chronic pain

Central sensitization caused by disinhibition of spinal cord circuits is a key mechanism of mechanical allodynia in neuropathic pain. Despite intense efforts, the molecular mechanisms that drive disinhibition and induce allodynia after peripheral nerve injury remain unclear. Using the spared-nerve injury (SNI) model of allodynia, we here demonstrate that SNI induces disinhibition of spinal nociceptive circuits by triggering homeostatic synaptic plasticity. Specifically, SNI-triggered homeostatic plasticity suppresses the inhibitory outputs of parvalbumin-positive (PV+) interneurons that form synapses on both primary afferent terminals and excitatory interneurons, causing hyperactivation of the nociceptive pathway. Using genetic manipulations, we identified the retinoic acid receptor RARα as the key mediator of the homeostatic synaptic plasticity underlying this synaptic disinhibition. Deletion of RARα in PV+ neurons blocked SNI-induced spinal disinhibition, central sensitization, and allodynia. Moreover, deletion of RARα in spinal PV+ neurons or application of an RARα antagonist in the spinal cord prevented the development of SNI-induced mechanical allodynia. Together, our results reveal a molecular mechanism of neuropathic pain whereby homeostatic plasticity causes the mis-direction of tactile information flow to ascending nociceptive pathways following peripheral nerve injury.

Therapeutic Low-Intensity Ultrasound for Peripheral Nerve Regeneration – A Schwann Cell Perspective

Peripheral nerve injuries are common conditions that can arise from trauma (e.g., compression, severance) and can lead to neuropathic pain as well as motor and sensory deficits. Although much knowledge exists on the mechanisms of injury and nerve regeneration, treatments that ensure functional recovery following peripheral nerve injury are limited. Schwann cells, the supporting glial cells in peripheral nerves, orchestrate the response to nerve injury, by converting to a “repair” phenotype. However, nerve regeneration is often suboptimal in humans as the repair Schwann cells do not sustain their repair phenotype long enough to support the prolonged regeneration times required for successful nerve regrowth. Thus, numerous strategies are currently focused on promoting and extending the Schwann cells repair phenotype. Low-intensity ultrasound (LIU) is a non-destructive therapeutic approach which has been shown to facilitate peripheral nerve regeneration following nerve injury in rodents. Still, clinical trials in humans are scarce and limited to small population sizes. The benefit of LIU on nerve regeneration could possibly be mediated through the repair Schwann cells. In this review, we discuss the known and possible molecular mechanisms activated in response to LIU in repair Schwann cells to draw support and attention to LIU as a compelling regenerative treatment for peripheral nerve injury.

Relationship of Anti-interleukin-6 Receptor Antibody to Interleukin-6 Level and Inducible Nitrite Oxide Levels in Peripheral Nerve Injury in Chronic Constriction Injury-Induced Rats: A Case-Control Study in Indonesia

BACKGROUND: Interleukin-6 (IL-6) and inducible Nitric oxide Synthase (iNOS) have an effect on neuropathic pain in the inflammatory process in peripheral nerve injuries. AIM: This study aims to examine the effect of anti-IL-6 receptor antibody on IL-6 and iNOS levels as a consideration for the treatment of neuropathic pain in a rat model of peripheral nerve injury. METHODS: Twenty-eight young adult male Wistar rats were treated for peripheral nerve injury and then divided into two groups. Fourteen treatment groups (Group P) were given anti-IL-6 receptor antibody by injection at a dose of 100 g/day by injection into the saphenous vein in the rat’s leg for 3 days. In both groups, the serum IL-6 and iNOS levels were assessed on the 3rd day after administration of anti-IL-6 receptor antibody in group P, using the sandwich ELISA method. RESULTS: The results showed that the administration of anti-IL-6 receptor antibody did not have a significant effect on reducing IL-6 and iNOS levels in group P (p > 0.05). Administration of anti-IL-6 receptor antibody had more effect on IL-6 levels on iNOS levels, where a decrease in IL-6 levels caused a decrease in iNOS levels in group P (p = 0.004 and r = 0.693). CONCLUSIONS: We conclude that the present administration of anti-IL-6 receptor antibody cannot be considered as a treatment for neuropathic pain in peripheral nerve injuries, but can be used to influence IL-6 levels on iNOS levels.

Graphene-Based Materials Prove to Be a Promising Candidate for Nerve Regeneration Following Peripheral Nerve Injury

Peripheral nerve injury is a common medical condition that has a great impact on patient quality of life. Currently, surgical management is considered to be a gold standard first-line treatment; however, is often not successful and requires further surgical procedures. Commercially available FDA- and CE- approved decellularized nerve conduits offer considerable benefits to patients suffering from a completely transected nerve but they fail to support neural regeneration in gaps >30 mm. To address this unmet clinical need, current research is focused on biomaterial-based therapies to regenerate dysfunctional neural tissues, specifically damaged peripheral nerve, and spinal cord. Recently, attention has been paid to the capability of graphene-based materials (GBMs) to develop bifunctional scaffolds for promoting nerve regeneration, often via supporting enhanced neural differentiation. The unique features of GBMs have been applied to fabricate an electroactive conductive surface in order to direct stem cells and improve neural proliferation and differentiation. The use of GBMs for nerve tissue engineering (NTE) is considered an emerging technology bringing hope to peripheral nerve injury repair, with some products already in preclinical stages. This review assesses the last six years of research in the field of GBMs application in NTE, focusing on the fabrication and effects of GBMs for neurogenesis in various scaffold forms, including electrospun fibres, films, hydrogels, foams, 3D printing, and bioprinting.