Analgesia research peptide

Anti-nociceptive effects of dual neuropeptide antagonist therapy in mouse model of neuropathic and inflammatory pain

Korean J Pain 2022; 35(2): 173-182

Published online April 1, 2022

Copyright © The Korean Pain Society.

Abstract

Background:

Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins’ antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the antinociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens.

Methods:

C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection.

Results:

Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds.

Conclusions:

A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.

Keywords:

Analgesics, Anxiety, Calcitonin Gene-Related Peptide Receptor Antagonists, Hyperalgesia, Neuralgia, Neurokinin-1 Receptor Antagonists, Neuropeptides, Nociception, Pain.

INTRODUCTION

Chronic pain is one of the most costly health problem across the world. Neuropathic pain is one of the leading causes of chronic pain, and it has been estimated to affect 7%–10% of the general population. Gabapentinoids, antidepressants, and even potent opioids have been widely prescribed to treat neuropathic pain. However, many patients do not achieve satisfactory pain relief with evidence-based treatments, such as traditional analgesics, or cannot tolerate these drugs because of their adverse effects. Recent advances in the understanding of the chronic pain have spurred an increased interest in the role of neuropeptides. Substance P (SP) and calcitonin gene-related peptide (CGRP) are the most widely investigated neuropeptides with potential roles in nociception that provide therapeutic targets.

Neurokinin-1 (NK1) antagonists for pain therapy were largely based on the concept of interrupting neurotransmission of SP from primary afferent nociceptors to central pain pathways in the spinal dorsal horn and more rostrally. Recent studies of neuropathic pain models have demonstrated that sustained activation of the NK1 receptor maintains pain hypersensitivity, and that NK1 receptor antagonists inhibit SP-induced activation of spinal neurons and thus prevent pain transmission in preclinical studies. Administration of NK1 receptor antagonists also demonstrated significant antinociceptive effects in the inflammatory pain model. Similar to the SP-NK1 receptor system, CGRP plays a role in transmission and modulation of pain signals. Administration of a CGRP receptor antagonist has been reported to prevent the development and maintenance of allodynia/hyperalgesia in rats suffering from neuropathic pain. Recent studies show apparent antinociceptive effects by CGRP antagonists in inflammatory pain models.

Current pharmacological regimens used in pain clinics to treat neuropathic pain frequently include a combination of multiple agents, such as antidepressants, gabapentin, analgesics, and antiepilepsy medications. The use of numerous pharmacological treatment strategies involving various medications can increase the success rate of neuropathic pain alleviation and minimize the adverse effects of each drug. Agents that block neuropeptide receptors are promising analgesic drug candidates; thus, several studies on the effects of neuropeptide antagonists combined with other pain medicines have been conducted. For example, Michot et al. reported that compared with the administration of each drug individually, the combination of naratriptan and a CGRP receptor antagonist more effectively alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve in rats. However, few studies have investigated the pain-alleviating effect of the combination of two or more neuropeptide antagonists.

Therefore, we investigated the anti-nociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist to 1) naive mice, 2) neuropathic pain models, and 3) inflammatory pain models, respectively.

MATERIALS AND METHODS

Content for Materials and Methods would be placed here.