Spinal Glia-Driven Neuroinflammation as a Therapeutic Target for Neuropathic Pain: Rational Development of Novel Analgesics.

Neuropathic pain caused by a lesion or disease of the somatosensory nervous system is a suffering and prevalent chronic pain condition with a major impact on the quality of patients' lives. Current pharmacotherapeutic interventions deliver insufficient pain relief, and thus the development of effective analgesics for neuropathic pain represents a significant clinical demand. Notably, accumulating evidence demonstrates that neuroinflammation mediated by microglia and astrocytes within the central nervous system plays a pivotal role in driving the pathological progression of neuropathic pain. Nerve injury or neuropathy triggers alterations in receptor and ion channel expression on microglia and astrocytes, including upregulation or downregulation. These alterations drive glial proliferation, mediate neuroinflammatory cascades, and facilitate the progression of neuropathic pain. In preclinical studies, clinical drugs or analgesic molecules targeting these glial receptors or ion channels have demonstrated significant neuropathic pain relief and suppression of neuroinflammation. The suppression includes inhibition of gliosis, reduction of pro-inflammatory mediator release, and transition toward anti-inflammatory microglia or neuroprotective astrocytes. Therefore, targeting glial receptors or ion channels involved in neuropathic pain to inhibit neuroinflammatory progression represents a promising therapeutic strategy for developing analgesics with potential long-term pharmacotherapy.