Semaphorins and Their Role in Neuropathic Pain

Neuropathic pain is a debilitating condition arising from lesions or diseases affecting the somatosensory nervous system. Despite significant advances in understanding its pathophysiology, the molecular mechanisms underlying the development and persistence of neuropathic pain remain incompletely understood. Semaphorins, a highly conserved family of axon guidance molecules, have emerged as key regulators of neuronal development, synaptic plasticity, immune responses, and neurovascular interactions. Beyond their roles during nervous system development, accumulating evidence indicates that semaphorins and their receptors, including plexins and neuropilins, actively participate in the pathological processes associated with peripheral and central sensitization following nerve injury. Altered semaphorin signaling has been implicated in neuroinflammation, aberrant axonal regeneration, glial cell activation, and dysregulated nociceptive transmission, thus contributing to the initiation and maintenance of neuropathic pain. Furthermore, several semaphorin family members show different effects, highlighting their multifaceted functions within the injured nervous system. This review summarizes the current understanding of semaphorin-mediated mechanisms involved in neuropathic pain and explores their interactions with inflammatory and neuroimmune pathways. A deeper understanding of semaphorin signaling might provide novel insights into the pathogenesis of neuropathic pain and facilitate the development of more effective treatment strategies.