Resveratrol alleviates neuropathic pain after spinal cord injury by suppressing δ-catenin palmitoylation-mediated membrane accumulation of Nav1.6 in the spinal dorsal horn

Neuropathic pain is a severe adverse complication of spinal cord injury (SCI) for which effective therapies are currently lacking. Resveratrol, a natural phytoalexin found in many plants and fruits, has been shown to relieve chemotherapy- and nerve injury-induced neuropathic pain and to promote functional recovery after SCI. In this study, we found that intraperitoneal administration of resveratrol increased the expression and activity of silent information regulator 1 (SIRT1) in the rat spinal dorsal horn and markedly attenuated neuropathic pain after SCI while improving motor recovery. Building on our previous finding that palmitoylation of δ-catenin promotes the membrane trafficking of the voltage-gated sodium channel Nav1.6 in dorsal root ganglion neurons and contributes to oxaliplatin- and nerve injury-induced neuropathic pain, we further examined whether resveratrol produces analgesia by inhibiting δ-catenin palmitoylation-mediated membrane accumulation of Nav1.6 in the spinal dorsal horn after SCI. Our results showed that SCI markedly increased both Nav1.6 membrane localization and δ-catenin palmitoylation in the dorsal horn and intrathecal delivery of Nav1.6 shRNA or pharmacological inhibition of palmitoylation with 2-bromopalmitate significantly attenuated mechanical allodynia after SCI. Resveratrol suppressed SCI-induced δ-catenin palmitoylation and reduced the pathological membrane accumulation of Nav1.6, an effect accompanied by downregulation of the palmitoyl acyltransferase ZDHHC3 (DHHC3). Together, these findings indicate that resveratrol alleviates neuropathic pain after SCI by inhibiting DHHC3-mediated δ-catenin palmitoylation and thereby suppressing the membrane trafficking of Nav1.6 in the spinal dorsal horn.