• Jinyuan Li, Gang Wang, Yiqi Weng, Mei Ding, and Wenli Yu.
• Department of Anesthesiology, Tianjin First Center Hospital, Tianjin 300192, China.
• Neurosci. Lett. 2020 Sep 14; 735: 135161.

BackgroundThe burden of neuropathic pain is growing worldwide. Recent studies recapitulate the requirement for AMPA receptor in excitatory synaptic plasticity underlying pain-related syndromes. Netrin-1 and its receptor deleted in colorectal cancer (DCC) are fundamental for AMPA receptor dependent synaptic transmission. Phosphatidylinositol 4-kinase IIa (Pi4KIIa) mediates post-synaptic insertion of AMPA receptor in neuropathic disorders. This study investigates whether netrin-1 and Pi4KIIa regulate peripheral nerve injury-induced neuropathic pain.MethodsA model of chronic constriction injury (CCI) of the sciatic nerve in mice was established to induce neuropathic pain. Paw withdrawal mechanical threshold, paw withdrawal thermal latency, spinal netrin-1 secretion, DCC level and Pi4KIIa expression were examined. Netrin-1 knockdown by shRNA, recombinant netrin-1 and Pi4KIIa inhibitor were employed to elucidate the substantial mechanisms.ResultsCCI surgery initiated and sustained the persistent reduction in paw withdrawal mechanical threshold and paw withdrawal thermal latency, along with the increase in spinal netrin-1 release, DCC level and Pi4KIIa expression. Netrin-1 deficiency impaired CCI-induced neuropathic pain behaviors and spinal over-expression of DCC and Pi4KIIa. Pharmacological inhibition of Pi4KIIa attenuated peripheral nerve injury induced mechanical allodynia and thermal hyperalgesia in a dose-dependent manner. Spinal application of recombinant netrin-1 caused pain hypersensitivity and up-regulated spinal expression of DCC and Pi4KIIa. Central inhibition of Pi4KIIa reversed exogenous netrin-1 evoked acute pain phenotype.ConclusionOur current results demonstrate the contribution of spinal netrin-1 and DCC in modulating the expression of Pi4KIIa in the pathogenesis of neuropathic pain in mice.Copyright © 2020 Elsevier B.V. All rights reserved.

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