Spinal microglial β-endorphin signaling mediates IL-10 and exenatide-induced inhibition of synaptic plasticity in neuropathic pain

Aim: This study aimed to investigate the regulation of pain hypersensitivity induced by the spinal synaptic transmission mechanisms underlying interleukin (IL)-10 and glucagon-like peptide 1 receptor (GLP-1R) agonist exenatide-induced pain anti-hypersensitivity in neuropathic rats through spinal nerve ligations. Methods: Neuropathic pain model was established by spinal nerve ligation of L5/ L6 and verified by electrophysiological recording and immunofluorescence staining. Microglial expression of beta-endorphin through autocrine IL-10-and exenatide-induced inhibition of glutamatergic transmission were performed by behavioral tests coupled with whole-cell recording of miniature excitatory postsynaptic currents (mEPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) through application of endogenous and exogenous IL-10 and beta-endorphin. Results: Intrathecal injections of IL-10, exenatide, and the mu-opioid receptor (MOR) agonists beta-endorphin and DAMGO inhibited thermal hyperalgesia and mechanical allodynia in neuropathic rats. Whole-cell recordings of bath application of exenatide, IL-10, and beta-endorphin showed similarly suppressed enhanced frequency and amplitude of the mEPSCs in the spinal dorsal horn neurons of laminae II, but did not reduce the frequency and amplitude of mIPSCs in neuropathic rats. The inhibitory effects of IL-10 and exenatide on pain hypersensitive behaviors and spinal synaptic plasticity were totally blocked by pretreatment of IL-10 antibody, beta-endorphin antiserum, and MOR antagonist CTAP. In addition, the microglial metabolic inhibitor minocycline blocked the inhibitory effects of IL-10 and exenatide but not beta-endorphin on spinal synaptic plasticity. Conclusion: This suggests that spinal microglial expression of beta-endorphin mediates IL-10-and exenatide-induced inhibition of glutamatergic transmission and pain hypersensitivity via presynaptic and postsynaptic MORs in spinal dorsal horn.

Automated summary

This study investigated the regulation of pain hypersensitivity by IL-10 and GLP-1R agonist exenatide in neuropathic rats, showing that spinal microglial expression of beta-endorphin mediates the inhibitory effects.