Zerumbone alleviates chronic constriction injury-induced allodynia and hyperalgesia through serotonin 5-HT receptors

Abstract

Zerumbone, a bioactive sesquiterpene isolated from Zingiber zerumbet (Smith), has shown to exert antiallodynic and antihyperalgesic effects in neuropathic pain mice model in our recent study. The mechanism through which zerumbone alleviates neuropathic pain has yet to be elucidated. Thus, this study aimed to determine whether the serotonergic system, part of the descending pain modulation pathway, contributes to the antineuropathic effect of zerumbone. Participation of the serotonergic system in zerumbone-induced antiallodynia and antihyperalgesia was assessed using Dynamic Plantar Aesthesiometer von Frey test and Hargreaves plantar test respectively in chronic-constriction injury mice model. Administration of ρ-chlorophenylalanine (PCPA, 100mg/kg, i.p.) for four consecutive days to deplete serotonin (5-HT) prior to zerumbone administration blocked the antiallodynic and antihyperalgesic effects of zerumbone. Further investigation with 5-HT receptor antagonists methiothepin (5-HT receptor antagonist, 0.1mg/kg), WAY-100635 (5-HT receptor antagonist, 1mg/kg), isamoltane (5-HT receptor antagonist, 2.5mg/kg), ketanserin (5-HT receptor antagonist, 0.3mg/kg) and ondansetron (5-HT receptor antagonist, 0.5mg/kg) managed to significantly attenuate antiallodynic and antihyperalgesic effects of zerumbone (10mg/kg). These findings demonstrate that zerumbone alleviates mechanical allodynia and thermal hyperalgesia through the descending serotonergic system via 5-HT receptors 1A, 1B, 2A, 3, 6 and 7 in chronic constriction injury neuropathic pain mice.

Zerumbone Modulates α2A-Adrenergic, TRPV1, and NMDA NR2B Receptors Plasticity in CCI-Induced Neuropathic Pain In Vivo and LPS-Induced SH-SY5Y Neuroblastoma In Vitro Models

“…Zerumbone has been shown to possess anti-inflammatory (Chien et al, 2008;Sulaiman et al, 2010a), antinociceptive (Sulaiman et al, 2010b), chemopreventive (Murakami et al, 1999), antimicrobial, and anti-oxidative properties (Habsah et al, 2000). Most importantly, we have reported the anti-allodynic and antihyperalgesic properties of zerumbone in a neuropathic pain mouse model (Zulazmi et al, 2015;Chia et al, 2016;Zulazmi et al, 2017).…”

“…We have previously demonstrated the antinociceptive properties of zerumbone in the chronic constriction injury neuropathic pain mice model and its mechanisms through serotoninergic (Chia et al, 2016) and the L-arginine-nitric oxide (Zulazmi et al, 2017) pathways. With this study, we now show that the noradrenergic system and excitatory receptors are crucial to zerumbone's anti-allodynic and antihyperalgesic properties.…”

“…As we have already shown the involvement of serotonergic system in the anti-neuropathic properties of zerumbone (Chia et al, 2016), this study will further explore the noradrenergic receptors of the monoaminergic system. Projections of noradrenergic neurons to the spinal cord arise from the pontine nuclei, mainly the A5, A6 (locus coeruleus), and A7 (Kölliker-Füse).…”

“…Compound extraction and isolation were conducted as previously reported (Chia et al, 2016). Zerumbone was dissolved in dimethylsulfoxide (DMSO), Tween 20 and normal saline (0.99% NaCl) in a ratio of 5:5:90 (v/v).…”

“…The final concentration of DMSO did not exceed 5% of the total volume and caused no detectable effect on its own. Zerumbone was administered at 10 mg/kg through the intraperitoneal route based on our previous studies (Zulazmi et al, 2015;Chia et al, 2016;Zulazmi et al, 2017). The dosage of zerumbone (10 mg/kg) was chosen based on previous studies published by our colleagues Zulazmi et al (2015), where they found zerumbone at 10 mg/kg was sufficient to provide anti-allodynic and antihyperalgesic properties in the CCI-induced neuropathic pain mice model.…”