Abstract
Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been proven to possess antinociceptive activity that works via the opioid and NO-dependent/cGMP-independent pathways. In the present study, we aimed to further determine the possible mechanisms of antinociception of MECN using various nociceptive assays. The antinociceptive activity of MECN was (i) tested against capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged against selective antagonist of opioid receptor subtypes (β-funaltrexamine, naltrindole, and nor-binaltorphimine); (iii) prechallenged against antagonist of nonopioid systems, namely, α2-noradrenergic (yohimbine), β-adrenergic (pindolol), adenosinergic (caffeine), dopaminergic (haloperidol), and cholinergic (atropine) receptors; (iv) prechallenged with inhibitors of various potassium channels (glibenclamide, apamin, charybdotoxin, and tetraethylammonium chloride). The results demonstrated that the orally administered MECN (100, 250, and 500 mg/kg) significantly (p < 0.05) reversed the nociceptive effect of all models in a dose-dependent manner. Moreover, the antinociceptive activity of 500 mg/kg MECN was significantly (p < 0.05) inhibited by (i) antagonists of μ-, δ-, and κ-opioid receptors; (ii) antagonists of α2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and (iii) blockers of different K+ channels (voltage-activated-, Ca2+-activated, and ATP-sensitive-K+ channels, resp.). In conclusion, MECN-induced antinociception involves modulation of protein kinase C-, bradykinin-, TRVP1 receptors-, and glutamatergic-signaling pathways; opioidergic, α2-noradrenergic, β-adrenergic, adenosinergic, dopaminergic, and cholinergic receptors; and nonopioidergic receptors as well as the opening of various K+ channels. The antinociceptive activity could be associated with the presence of several flavonoid-based bioactive compounds and their synergistic action with nonvolatile bioactive compounds.
Highlights
An unpleasant experience caused by intense or damaging stimuli, is primarily protective in nature and can act as a sensorial modality to indicate the presence of tissues injury [1, 2]. ere are various types and causes of pain, but all relate to a sensation of physical or emotional discomfort that affects daily routine negatively
E management of pain using currently available analgesics could not completely thrive in relieving pain due to the fact that pain modulation is an intricate process involving many mediators and receptors at the peripheral and central levels. e sensitivity of nociceptive neuron is adjusted by a large variety of mediators in the extracellular space. ese mediators, either neurotransmitters or neuromodulators, activate a large number of receptor classes, which in turn activate a plethora of signaling cascades that are responsible for controlling the perception of pain [4,5,6,7]
E ect of methanol extract of C. nutans (MECN) on Capsaicin, Glutamate, Phorbol 12-Myristate 13-Acetate- (PMA-), and Bradykinin-Induced Nociception. e e ect of MECN on capsaicin-induced nociception in mice is shown in Figure 1. e oral administration of MECN (100, 250, and 500 mg/kg) produced signi cant (p < 0.001) and dose-related inhibition of the capsaicin-induced neurogenic pain
Summary
An unpleasant experience caused by intense or damaging stimuli, is primarily protective in nature and can act as a sensorial modality to indicate the presence of tissues injury [1, 2]. ere are various types and causes of pain, but all relate to a sensation of physical or emotional discomfort that affects daily routine negatively. Ese mediators, either neurotransmitters or neuromodulators, activate a large number of receptor classes, which in turn activate a plethora of signaling cascades that are responsible for controlling the perception of pain [4,5,6,7]. E management of pain using currently available analgesics could not completely thrive in relieving pain due to the fact that pain modulation is an intricate process involving many mediators and receptors at the peripheral and central levels. How this multitude of cascades mediates nociceptor sensitization and pain is only beginning to be understood. Available analgesics relieve pain as a symptom without affecting its cause [9]. erefore, search for new analgesic drugs with promising pharmacological actions has become an urgent need
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