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

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.

Peripheral ablation of type III adenylyl cyclase induces hyperalgesia and eliminates KOR-mediated analgesia in mice

“…A prominent mechanism underlying peripheral opioid analgesia is the activation of potassium channels in DRG neurons ( 42 , 43 ). Therefore, we examined the effect of KOR agonists on Kv channels in control and AC3 -CKO DRG neurons.…”

Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models

“…Both these systems have been fairly investigated in comparison to other systems involved in the pain pathway. We have elucidated the involvement of the serotonergic system in zerumbone's anti-allodynic and antihyperalgesic effects [24], with recent findings showing the involvement of the adrenergic and opioidergic systems, TPRV, NMDA, and potassium receptors [25,26]. Further investigation should be conducted to understand zerumbone's mechanism of action against neuropathic pain.…”

“…The Hargreaves Plantar Test apparatus (Ugo Basile, Italy), based on Hargreaves, et al [75], was used to measure thermal hyperalgesia, with slight modifications [26,76]. The animals were allowed to acclimatize in individual clear boxes placed on a raised glass podium.…”

Healthy Zerumbone: From Natural Sources to Strategies to Improve Its Bioavailability and Oral Administration

“…Zerumbone was able to exert antiallodynic and anti-hyperalgesic effects in a mouse model of neuropathic pain through inhibition of the serotonergic system, specifically 5-HT receptor subtypes 1A 1B, 2A, 3, 6 and 7 [ 24 ]. More recent studies indicate that in the antiallodynic and anti-hyperalgesic effects of zerumbone, K + channels and µ-, δ- and κ-opioid receptor subtypes [ 25 ], as well as cannabinoids and peroxisome proliferator-activated receptors (PPARs), are involved [ 26 ] in its modulation of neuropathic pain. In addition, the anti-hyperglycemic and anti-hyperlipidemic effects of zerumbone have beneficial effects in reducing the risk of diabetic retinopathy [ 27 ], and the dual acetylcholinesterase and butyrylcholinesterase inhibitory activity of zerumbone with high permeability across the blood-brain barrier supports its benefits as a preventive agent in Alzheimer’s disease [ 28 ].The pharmacokinetic properties of zerumbone explain the low bioavailability and distribution in the body of this water-insoluble compound.…”