Background: The 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.

Methods: A 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.

Results: CCI 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.

Conclusion: Our 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.