Spinal protein kinase Mζ contributes to the maintenance of peripheral inflammation-primed persistent nociceptive sensitization after plantar incision

BackgroundPrevious studies suggest that persistent post-surgical pain (PPSP) is correlated with preoperative pain status and amplification of central sensitization. Protein kinase M (PKM) 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 to PPSP, a condition in which preoperative pain is prevalent, are not known. MethodsHere, a modified hyperalgesia priming' model was established to simulate the clinical situation. This model used intraplantar injections of carrageenan (Car) as priming stimuli to elicit persistent nociceptive sensitization after plantar incision in rats. Upon treatment with PKM inhibitor ZIP, Scr-ZIP or protein kinase Cs (PKCs) inhibitor NPC-15437, altered behaviour and spinal PKM/PKCs expression were observed. ResultsA long-lasting hypersensitivity induced by Car-priming was identified and precipitated by subsequent plantar incision in this two-hit' paradigm. Post-treatment with ZIP, but not Scr-ZIP and NPC-15437, after the resolution of Car-priming selectively relieved hypersensitivity. In contrast, pre-priming NPC-15437 treatment only prevented Car-induced initial transient hyperalgesia. Immunoassays showed a significant decrease in spinal PKM expression after plantar incision with post-priming ZIP treatment as compared with Scr-ZIP and NPC-15437, but no notable differences in PKCs expression were observed. ConclusionsSpinal PKCs solely contribute to the initial induction of persistent pain, whereas PKM plays an essential role in spinal plasticity storage. PKM is responsible for the maintenance of peripheral inflammation-primed PPSP. Therefore, spinal PKM may be a therapeutic target to prevent surgery-induced chronic pain in patients with preoperative pain.