Red nucleus IL-15 facilitates the development of neuropathic pain in male rats by inducing inflammatory factors: implying the involvement of NF-κB and p38 MAPK

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Our recent studies have identified that the red nucleus (RN), a prominent motor regulatory nucleus situated in the midbrain tegmentum, is involved in the development of neuropathic pain. However, the molecular mechanisms by which the RN mediates pain regulation are still far from clear. Here, we report that the RN modulates neuropathic pain through secreting IL-15, a member of the immunomodulatory cytokine family. Following spared nerve injury (SNI) of male rats, IL-15 and its receptor IL-15Rα were boosted in the RN, especially within neurons and microglia, during the development stage of neuropathic pain. Knockdown of red nucleus IL-15 alleviated SNI-induced neuropathic pain, whereas intrarubral administration of exogenous IL-15 evoked abnormal pain in naive rats. Further studies indicated that red nucleus IL-15 exerted algesic effect by inducing the production of inflammatory factors, including cytokines TNF-α and IL-1β, chemokine CXCL11, and complement component C4a. Blockade of these inflammatory factors alleviated IL-15-mediated neuropathic pain. Additionally, our data demonstrated that NF-κB and p38 MAPK signaling pathways were involved in red nucleus IL-15-mediated neuropathic pain, in which p38 MAPK pathway contributed to IL-15-induced release of TNF-α and IL-1β, while both NF-κB and p38 MAPK pathways contributed to IL-15-induced secretion of CXCL11 and C4a. Inhibition of red nucleus NF-κB or p38 MAPK suppressed the upregulation of TNF-α, IL-1β, CXCL11 and/or C4a, and alleviated red nucleus IL-15-mediated neuropathic pain. These findings provide mechanistic insights by which red nucleus IL-15 facilitates the development of neuropathic pain and highlight its potential as a therapeutic target for refractory neuropathic pain.