Inhibition of Mitogen-Activated Protein Kinases Phosphorylation Plays an Important Role in the Anti-nociceptive Effect of Pregabalin in Zymosan-Induced Inflammatory Pain Model

Although pregabalin has been shown to have preclinical and clinical efficacy in neuropathic pain, the mechanism of its antinociceptive action is still unknown in other pain states. This study aimed to evaluate the antinociceptive effect of pregabalin and its underlying spinal mechanisms related to mitogen activated protein kinases (MAPKs) in neuron and microglia following intraplantar injection of zymosan model. Zymosan evoked thermal hyperalgesia, mechanical hyperalgesia, and mechanical allodynia starting from 1 h and persistent until 5 h post-injection, which were dose-dependently reversed by oral pretreatment of pregabalin (3, 10, and 30 mg/kg). Pregabalin dramatically inhibited zymosan-induced Fos expression (a marker for neuronal activation) and microglia activation (using markers CD11b and ED1) in the spinal dorsal horn. Moreover, zymosan significantly increased phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 (double labeling with neuron), ERK5 (double labelling with neuron and microglia) and p38 MAPK (double labeling with microglia) in the spinal dorsal horn, which overall elevations were reversed by pregabalin. These findings suggest that blockage of MAPKs activation in neuron and microglia might be closely related to the antinociceptive effect of pregabalin on zymosan-induced peripheral inflammatory pain.