Activation of p38 and p42/44 MAP kinase in neuropathic pain: involvement of VPAC2 and NK2 receptors and mediation by spinal glia.

Activation of intracellular signaling pathways involving p38 and p42/44 MAP kinases may contribute importantly to synaptic plasticity underlying spinal neuronal sensitization. Inhibitors of p38 or p42/44 pathways moderately attenuated responses of dorsal horn neurons evoked by mustard oil but not brush and alleviated the behavioral reflex sensitization seen following nerve injury. Activation of p38 and p42/44 MAP kinases in spinal cord ipsilateral to constriction injury was reduced by antagonists of NMDA, VPAC2 and NK2 (but not related) receptors, the glial inhibitor propentofylline and inhibitors of TNF-alpha. A VPAC2 receptor agonist enhanced p38 phosphorylation and caused behavioral reflex sensitization in naïve animals that could be blocked by co-administration of p38 inhibitor. Conversely, an NK2 receptor agonist activated p42/44 and caused behavioral sensitization that could be prevented by co-administration of p42/44 inhibitor. Thus, spinal p38 and p42/44 MAP kinases are activated in neuropathic pain states by mechanisms involving VPAC2, NK2, NMDA receptors and glial cytokine production.