Homer1a inhibits caspase-6 signaling to attenuate inflammatory pain in the spinal dorsal horn

ObjectiveThis study aimed to investigate the effect of Homer1a on caspase-6/tumor necrosis factor-alpha signaling pathway in an inflammatory pain model. We sought to determine whether Homer1a could alleviate nociceptive hypersensitivity by inhibiting the activation of the caspase-6/tumor necrosis factor-alpha signaling pathway.MethodsAn inflammatory pain model was established by unilateral plantar injection of carrageenan in rats. The hypothesis was tested using behavioral and immunological approaches.ResultsIn rats with carrageenan-induced hind paw inflammation, pain hypersensitivity was exacerbated, accompanied by an upregulation of Homer1a and activation of the caspase-6/tumor necrosis factor-alpha signaling pathway. Intrathecal administration of the caspase-6 inhibitor Z-valine-glutamic acid-isoleucine-aspartic acid-fluoromethyl ketone significantly attenuated microglial activation, tumor necrosis factor-alpha release, and thermal hypersensitivity but had no effect on Homer1a expression. Lentiviral overexpression of Homer1a reduced pain hypersensitivity and concurrently inhibited the caspase-6/tumor necrosis factor-alpha signaling pathway.ConclusionsThe present study demonstrates that Homer1a activation suppresses the caspase-6/tumor necrosis factor-alpha signaling pathway and alleviates thermal hypersensitivity in a rat model of inflammatory pain. These findings suggest that the Homer1a/caspase-6 signaling axis may represent a promising therapeutic target for inflammatory pain management.