Neuropathic pain caused by nerve injury or disease remains a major challenge for modern medicine worldwide. Most of the pathogenic mechanisms underlying neuropathic pain are centered on neuronal mechanisms. Accumulating evidence suggests that non-neuronal cells, especially glial cells, also play active roles in the initiation and resolution of pain. The preponderance of evidence has implicated central nervous system (CNS) glial cells, i.e., microglia and astrocytes, in the control of pain. The role of Schwann cells in neuropathic pain remains poorly understood. Schwann cells, which detect nerve injury and provide the first response, play a critical role in the development and maintenance of neuropathic pain. The cells respond to nerve injury by changing their phenotype, proliferating and interacting with nociceptive neurons by releasing glial mediators (growth factors, cytokines, chemokines, and biologically active small molecules). In addition, receptors expressed in active Schwann cells have the potential to regulate different pain conditions. In this review article, we will provide and discuss emerging evidence by integrating recent advances related to Schwann cells and neuropathic pain.

Of the seven P2X receptor subtypes, P2X4 receptor (P2X4R) is widely distributed in the central nervous system, including in neurons, astrocytes, and microglia. Accumulating evidence supports roles for P2X4R in the central nervous system, including regulating cell excitability, synaptic transmission, and neuropathic pain. However, little information is available about the distribution and function of P2X4R in the peripheral nervous system. In this study, we find that P2X4R is mainly localized in the lysosomes of Schwann cells in the peripheral nervous system. In cultured Schwann cells, TNF‐a not only enhances the synthesis of P2X4R protein but also promotes P2X4R trafficking to the surface of Schwann cells. TNF‐a‐induced BDNF secretion in Schwann cells is P2X4R dependent. in vivo experiments reveal that expression of P2X4R in Schwann cells of injured nerves is strikingly upregulated following nerve crush injury. Moreover, overexpression of P2X4R in Schwann cells by genetic manipulation promotes motor and sensory functional recovery and accelerates nerve remyelination via BDNF release following nerve injury. Our results suggest that enhancement of P2X4R expression in Schwann cells after nerve injury may be an effective approach to facilitate the regrowth and remyelination of injured nerves.

Background Peripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI. Methods PNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents. Results MaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K–AKT–mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice. Conclusions Application of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.

Myelination by oligodendrocytes in the central nervous system requires coordinated exocytosis and endocytosis of the major myelin protein, proteolipid protein (PLP). Here, we demonstrated that a small GTPase, Rab27b, is involved in PLP trafficking in oligodendrocytes. We showed that PLP co-localized with Rab27b in late endosomes/lysosomes in oligodendrocytes. Short hairpin-mediated knockdown of Rab27b not only reduced lysosomal exocytosis but also greatly diminished the surface expression of PLP in oligodendrocytes. In addition, knockdown of Rab27b reduced the myelin-like membranes induced by co-culture of oligodendrocytes and neurons. Our data suggest that Rab27b is involved in myelin biogenesis by regulating PLP transport from late endosomes/lysosomes to the cell membrane in oligodendrocytes.

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