Spinal protein kinase M ζ contributes to the maintenance of peripheral inflammation‐primed persistent nociceptive sensitization after plantar incision

Background Previous studies suggest that persistent post‐surgical pain ( PPSP ) is correlated with preoperative pain status and amplification of central sensitization. Protein kinase M ζ ( PKM ζ) is an essential substrate of the late long‐term potentiation underlying central sensitization, which is one mechanism of pain memory formation. However, the potential contributions of spinal PKM ζ to PPSP , a condition in which preoperative pain is prevalent, are not known. Methods Here, a modified ‘hyperalgesia priming’ model was established to simulate the clinical situation. This model used intraplantar injections of carrageenan ( C ar) as priming stimuli to elicit persistent nociceptive sensitization after plantar incision in rats. Upon treatment with PKM ζ inhibitor ZIP , S cr‐ ZIP or protein kinase C s ( PKC s) inhibitor NPC ‐15437, altered behaviour and spinal PKM ζ/ PKC s expression were observed. Results A long‐lasting hypersensitivity induced by C ar‐priming was identified and precipitated by subsequent plantar incision in this ‘two‐hit’ paradigm. Post‐treatment with ZIP , but not S cr‐ ZIP and NPC ‐15437, after the resolution of C ar‐priming selectively relieved hypersensitivity. In contrast, pre‐priming NPC ‐15437 treatment only prevented C ar‐induced initial transient hyperalgesia. Immunoassays showed a significant decrease in spinal PKM ζ expression after plantar incision with post‐priming ZIP treatment as compared with S cr‐ ZIP and NPC ‐15437, but no notable differences in PKC s expression were observed. Conclusions Spinal PKC s solely contribute to the initial induction of persistent pain, whereas PKM ζ plays an essential role in spinal plasticity storage. PKM ζ is responsible for the maintenance of peripheral inflammation‐primed PPSP . Therefore, spinal PKM ζ may be a therapeutic target to prevent surgery‐induced chronic pain in patients with preoperative pain.