Zerumbone-Induced Analgesia Modulated via Potassium Channels and Opioid Receptors in Chronic Constriction Injury-Induced Neuropathic Pain

Banulata Gopalsamy,Mohd Roslan Sulaiman,Ahmad Akira Omar Farouk,Enoch Kumar Perimal,Jasmine Siew Min Chia

doi:10.3390/molecules25173880

Abstract

Zerumbone, a monocyclic sesquiterpene from the wild ginger plant Zingiber zerumbet (L.) Smith, attenuates allodynia and hyperalgesia. Currently, its mechanisms of action in neuropathic pain conditions remain unclear. This study examines the involvement of potassium channels and opioid receptors in zerumbone-induced analgesia in a chronic constriction injury (CCI) neuropathic pain mice model. Male Institute of Cancer Research (ICR) mice were subjected to CCI and behavioral responses were tested on day 14. Responses toward mechanical allodynia and thermal hyperalgesia were tested with von Frey’s filament and Hargreaves’ tests, respectively. Symptoms of neuropathic pain were significantly alleviated following treatment with zerumbone (10 mg/kg; intraperitoneal, i.p.). However, when the voltage-dependent K+ channel blocker tetraethylammonium (TEA, 4 mg/kg; i.p.), ATP-sensitive K+ channel blocker, glibenclamide (GLIB, 10 mg/kg; i.p.); small-conductance Ca2+-activated K+ channel inhibitor apamin (APA, 0.04 mg/kg; i.p.), or large-conductance Ca2+-activated K+ channel inhibitor charybdotoxin (CHAR, 0.02 mg/kg; i.p.) was administered prior to zerumbone (10 mg/kg; i.p.), the antiallodynic and antihyperalgesic effects of zerumbone were significantly reversed. Additionally, non-specific opioid receptors antagonist, naloxone (NAL, 10 mg/kg; i.p.), selective µ-, δ- and κ-opioid receptor antagonists; β-funaltrexamine (β-FN, 40 mg/kg; i.p.), naltrindole (20 mg/kg; s.c.), nor-binaltorphamine (10 mg/kg; s.c.) respectively attenuated the antiallodynic and antihyperalgesic effects of zerumbone. This outcome clearly demonstrates the participation of potassium channels and opioid receptors in the antineuropathic properties of zerumbone. As various clinically used neuropathic pain drugs also share this similar mechanism, this compound is, therefore, a highly potential substitute to these therapeutic options.

Highlights

Neuropathic pain occurs following a disease or injury to the peripheral and central nervous system.This chronic pain condition remains a therapeutic challenge in clinical settings, as modern therapies are only partially effective
To further understand the exact underlying mechanism of this compound, we aimed to investigate if zerumbone’s actions involve potassium channels and opioid receptors in a chronic constriction injury (CCI)-induced mice model of neuropathic pain
The involvement of voltage-dependent K+ channels in the antineuropathic properties of zerumbone was investigated by blocking the channels with a voltage-dependent K+ channel blocker, tetraethylammonium (TEA)

Summary

Introduction

Neuropathic pain occurs following a disease or injury to the peripheral and central nervous system.This chronic pain condition remains a therapeutic challenge in clinical settings, as modern therapies are only partially effective. Neuropathic pain occurs following a disease or injury to the peripheral and central nervous system. Various biochemical and pathophysiological changes occur following neural damage, which leads to a morphological and functional adaptation of the nervous system to external stimuli. This adaptation plays an essential role in the commencement and maintenance of pain symptoms. Even though this chronic pain state is mediated by both peripheral and central mechanisms, the pathological overexcitability of nociceptive afferents is often the trigger. Factors that lead to peripheral sensitization include sprouting of sympathetic nerves [1], inflammatory mechanisms [2], and altered activity or expression of various proteins that are related to neuronal excitability [3]

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