Abstract
BackgroundMethanol extract (MECN) of Clinacanthus nutans Lindau leaves (family Acanthaceae) demonstrated peripherally and centrally mediated antinociceptive activity via the modulation of opioid/NO-mediated, but cGMP-independent pathway. In the present study, MECN was sequentially partitioned to obtain petroleum ether extract of C. nutans (PECN), which was subjected to antinociceptive study with aims of establishing its antinociceptive potential and determining the role of opioid receptors and l–arginine/nitric oxide/cyclic-guanosine monophosphate (l–arg/NO/cGMP) pathway in the observed antinociceptive activity.MethodsThe antinociceptive potential of orally administered PECN (100, 250, 500 mg/kg) was studied using the abdominal constriction-, hot plate- and formalin-induced paw licking-test in mice (n = 6). The effect of PECN on locomotor activity was also evaluated using the rota rod assay. The role of opioid receptors was determined by pre-challenging 500 mg/kg PECN (p.o.) with antagonist of opioid receptor subtypes, namely β–funaltrexamine (β–FNA; 10 mg/kg; a μ-opioid antagonist), naltrindole (NALT; 1 mg/kg; a δ-opioid antagonist) or nor–binaltorphimine (nor–BNI; 1 mg/kg; a κ-opioid antagonist) followed by subjection to the abdominal constriction test. In addition, the role of l–arg/NO/cGMP pathway was determined by prechallenging 500 mg/kg PECN (p.o.) with l–arg (20 mg/kg; a NO precursor), 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 2 mg/kg; a specific soluble guanylyl cyclase inhibitor), or the combinations thereof (l–arg + ODQ) for 5 mins before subjection to the abdominal constriction test. PECN was also subjected to phytoconstituents analyses.ResultsPECN significantly (p < 0.05) inhibited nociceptive effect in all models in a dose-dependent manner. The highest dose of PECN (500 mg/kg) also did not significantly (p > 0.05) affect the locomotor activity of treated mice. The antinociceptive activity of PECN was significantly (p < 0.05) inhibited by all antagonists of μ-, δ-, and κ-opioid receptors. In addition, the antinociceptive activity of PECN was significantly (p < 0.05) reversed by l–arg, but insignificantly (p > 0.05) affected by ODQ. HPLC analysis revealed the presence of at least cinnamic acid in PECN.ConclusionPECN exerted antinocicpetive activity at peripheral and central levels possibly via the activation of non-selective opioid receptors and modulation of the NO-mediated/cGMP-independent pathway partly via the synergistic action of phenolic compounds.
Highlights
Pain is an essential sensation that plays a vital role as a body’s natural defence system by alerting us to possible tissue injury while nociception is described as “the neural processes of encoding and processing noxious stimuli” that usually leads to pain [1]
The process mentioned above is initiated by specialized peripheral sensory neurons that are activated by noxious stimuli due to tissue injury and damage, and these nociceptors are usually found in the cutaneous tissues, bone, muscle, connective tissues, vessels and viscera
A variety of excitatory neurotransmitters are released by the primary afferent neurons, such as excitatory amino acids, protons, peptides, lipids and cytokines, and others, which act on their specific receptors and ion channels, to activate the second order neurons of the spinal dorsal horn
Summary
Pain is an essential sensation that plays a vital role as a body’s natural defence system by alerting us to possible tissue injury while nociception is described as “the neural processes of encoding and processing noxious stimuli” that usually leads to pain [1]. The process mentioned above is initiated by specialized peripheral sensory neurons (nociceptors) that are activated by noxious stimuli (i.e., mechanical, thermal, and chemical stimuli) due to tissue injury and damage, and these nociceptors are usually found in the cutaneous tissues, bone, muscle, connective tissues, vessels and viscera. These stimuli are transduced into electrical impulses (action potentials) that are transmitted predominantly through Aδ- and C-fibre nociceptors (primary afferent neurons) into the dorsal horn of the spinal cord [1]. MECN was sequentially partitioned to obtain petroleum ether extract of C. nutans (PECN), which was subjected to antinociceptive study with aims of establishing its antinociceptive potential and determining the role of opioid receptors and L–arginine/nitric oxide/cyclic-guanosine monophosphate (L–arg/NO/cGMP) pathway in the observed antinociceptive activity
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