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

Abstract

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.Key words pregabalin; pain; mitogen activated protein kinase (MAPK); zymosan Pregabalin as a new-generation anti-epileptic drug with fewer side effects and less tolerance has been shown to have preclinical and clinical efficacy in neuropathic pain. Accumulative clinical studies in different types of neuropathic pain (i.e., peripheral diabetic neuropathy, fibromyalgia, postherpetic neuralgia, cancer chemotherapy-induced neuropathic pain) have demonstrated its effectiveness in treating the neurological symptoms including allodynia and hyperalgesia.1) In several type of neuropathic pain models, it has been further demonstrated that pregabalin has an influence on various neuronal targets and the signaling systems including calcium channel-mediated neurotransmitter release and activation of excitatory amino acid pathway in the spinal level.1) Despite widespread clinical use and characterization of antinociceptive activity of pregabalin in neuropathic pain, potential antinociceptive effect and its underlying molecular mechanisms in other pain state remain poorly understood. Thus, present study was focus on the potential antinociceptive effect of pregabalin in the peripheral inflammatory pain state.In recent years, microglia has been increasingly implicated in the mechanisms underlying abnormal pain states. Spinal microglia activation (using markers CD11b and ED1) has been observed in the early phase of neuropathic pain, 2) which is closely correlated with induction and maintenance of allodynia and hyperalgesia.3) In line with this view, microglia inhibitors successfully alleviate neuropathic pain in experimental models.3,4) Similar with neuropathic condition, peripheral inflammation...

MAPK Pathways Are Involved in Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

“…Additionally, JNK signaling plays a crucial role in mediating antinociception and chronic tolerance to the antinociceptive effects of morphine in acute, inflammatory, and neuropathic pain states [ 22 ]. The spinal activation mechanisms of MAPK signaling pathways in both neurons and microglia are involved in the antinociceptive effects of pregabalin in a zymosan-induced peripheral inflammatory pain model [ 23 ].…”

Effect of TRPV4-p38 MAPK Pathway on Neuropathic Pain in Rats with Chronic Compression of the Dorsal Root Ganglion

“…Furthermore, p38 reduces pain by inhibiting p38 phosphorylation through decreased TNF- α [ 10 ]. Pregabalin reduces the nociceptive reaction in a zymosan-induced inflammatory pain model by inhibiting the phosphorylation of MAPKs [ 11 ]. Considerable evidence indicates that p38 is an important mediator of the NF- κ B pathway, which might be inhibited by SB203580 through the NF- κ B pathway [ 12 , 13 ].…”

Research progress of the role and mechanism of extracellular signal-regulated protein kinase 5 (ERK5) pathway in pathological pain

“…Knockdown of ERK5 decreases the induction of TRPV1 and TRPA1 and inhibits the heat and cold hypersensitivity induced by SNI . In brief, activation of ERK5 contributes to pain hypersensitivity, while antisense knockdown of ERK5, where the effects are present both in DRG and the spinal cord, can suppress the nerve injury-induced mechanical allodynia and thermal hyperalgesia (Jeong et al, 2014). Taken together, these findings suggest that the activation of ERK5 in primary sensory neurons and the spinal cord plays a crucial role in the pathogenesis of inflammatory pain and neuropathic pain.…”