Antinociceptive Activity of Petroleum Ether Fraction ofClinacanthus nutansLeaves Methanolic Extract: Roles of Nonopioid Pain Modulatory Systems and Potassium Channels

Abstract

Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive mechanisms of a lipid-soluble fraction of MECN, which was obtained after sequential extraction in petroleum ether. The petroleum ether fraction of C. nutans (PECN), administered orally to mice, was (i) subjected to capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged (intraperitoneal (i.p.)) with 0.15 mg/kg yohimbine, 1 mg/kg pindolol, 3 mg/kg caffeine, 0.2 mg/kg haloperidol, or 10 mg/kg atropine, which were the respective antagonist of α2-adrenergic, β-adrenergic, adenosinergic, dopaminergic, or muscarinic receptors; and (iii) prechallenged (i.p.) with 10 mg/kg glibenclamide, 0.04 mg/kg apamin, 0.02 mg/kg charybdotoxin, or 4 mg/kg tetraethylammonium chloride, which were the respective inhibitor of ATP sensitive-, small conductance Ca2+-activated-, large conductance Ca2+-activated-, or nonselective voltage-activated-K+ channel. Results obtained demonstrated that PECN (100, 250, and 500 mg/kg) significantly (P<0.05) inhibited all models of nociception described earlier. The antinociceptive activity of 500 mg/kg PECN was significantly (P<0.05) attenuated when prechallenged with all antagonists or K+ channel blockers. However, only pretreatment with apamin and charybdotoxin caused full inhibition of PECN-induced antinociception. The rest of the K+ channel blockers and all antagonists caused only partial inhibition of PECN antinociception, respectively. Analyses on PECN’s phytoconstituents revealed the presence of antinociceptive-bearing bioactive compounds of volatile (i.e., derivatives of γ–tocopherol, α–tocopherol, and lupeol) and nonvolatile (i.e., cinnamic acid) nature. In conclusion, PECN exerts a non-opioid-mediated antinociceptive activity involving mainly activation of adenosinergic and cholinergic receptors or small- and large-conductance Ca2+-activated-K+ channels.

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

“…The antagonist’s modes of administration, dose, and duration of effect were pre-tested to ensure they did not increase pain or sensitivity in the animals prior to testing on the actual experimental animals. This protocol was reported by Ming-Tatt et al [ 92 ] and Zakaria et al [ 101 ].…”

From Plant to Chemistry: Sources of Active Opioid Antinociceptive Principles for Medicinal Chemistry and Drug Design

“…Pretreatment with naloxone blocked its effects in all three pain models, suggesting the involvement of opioid receptors. The lipid-soluble fraction of methanolic extract, obtained after its sequential extraction in a petroleum ether, was also investigated to determine the possible involvement of a non-opioid mechanism [130]. P.o.-tested, it showed the possible involvement of TRPV1-, NMDA-, B2-receptors, and a PKC-activated TRPV1 receptor pathway because of the petroleum ether extract's capability to attenuate capsaicin-, glutamate-, PMA-, and bradykinin-induced nociception.…”