GPR55 activation alleviates cognitive dysfunction caused by neuropathic pain through modulation of microglia polarization and synaptic plasticity via the CaMKKβ/AMPK/SOCS3 signaling pathway.

Cognitive impairment induced by neuropathic pain substantially diminishes quality of life, with hippocampal neuroinflammation identified as a critical pathogenic factor. Although G protein-coupled receptor 55 (GPR55) demonstrates anti-inflammatory, analgesic, and neuroprotective properties, its therapeutic potential and molecular mechanisms in neuropathic pain-induced cognitive deficits remain uncharacterized. Using a spared nerve injury (SNI) mouse model, we systematically investigated GPR55's neuroprotective mechanisms. Pharmacological activation of GPR55 effectively ameliorated cognitive dysfunction and attenuated hippocampal neuroinflammation and preserved synaptic plasticity by shifting microglial polarization toward the neuroprotective M2 phenotype in SNI mice. Mechanistic studies revealed that the immunomodulatory effects operate through the CaMKKβ/AMPK/SOCS3 signaling axis, as confirmed by pathway blockade using the specific inhibitor Compound C. These results demonstrate that GPR55 activation modulates microglial polarization, mitigates neuroinflammatory cascades, and preserves synaptic plasticity, thus alleviating neuropathic pain-associated cognitive dysfunction through a mechanism involving the CaMKKβ/AMPK/SOCS3 signaling pathway.