Antinociceptive Action of Isolated Mitragynine from Mitragyna Speciosa through Activation of Opioid Receptor System (original) (raw)
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British Journal of Pharmacology, 2008
Background and purpose:Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of μ-, δ- and κ-opioid receptors.Although participation of opioids in antinociception induced by cannabinoids has been documented, there is little information regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids could be involved in peripheral antinociception induced by activation of μ-, δ- and κ-opioid receptors.Experimental approach:Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 μg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 μg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 μg), bremazocine (50 μg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4- iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20–80 μg), 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5–100 μg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1–4 μg) were also injected in the paw.Nociceptive thresholds to mechanical stimulation of rat paws treated with intraplantar prostaglandin E2 (PGE2, 2 μg) to induce hyperalgesia were measured 3 h after injection using an algesimetric apparatus. Opioid agonists morphine (200 μg), (+)-4-[(alphaR)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC80) (80 μg), bremazocine (50 μg); cannabinoid receptor antagonists N-(piperidin-1-yl)-5-(4- iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) (20–80 μg), 6-iodo-2-methyl-1-[2-(4-morpholinyl) ethyl]-1H-indol-3-yl(4-methoxyphenyl) methanone (AM630) (12.5–100 μg); and an inhibitor of methyl arachidonyl fluorophosphonate (MAFP) (1–4 μg) were also injected in the paw.Key results:The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect.The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the peripheral antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 elicited partial antagonism of this effect. In addition, the administration of the fatty acid amide hydrolase inhibitor, MAFP, enhanced the antinociception induced by morphine. The cannabinoid receptor antagonists AM251 and AM630 did not modify the antinociceptive effect of SNC80 or bremazocine. The antagonists alone did not cause any hyperalgesic or antinociceptive effect.Conclusions and implications:Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the μ-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by κ- and δ-opioid receptor agonists.British Journal of Pharmacology (2008) 154, 1143–1149; doi:10.1038/bjp.2008.175; published online 12 May 2008Our results provide evidence for the involvement of endocannabinoids, in the peripheral antinociception induced by the μ-opioid receptor agonist morphine. The release of cannabinoids appears not to be involved in the peripheral antinociceptive effect induced by κ- and δ-opioid receptor agonists.British Journal of Pharmacology (2008) 154, 1143–1149; doi:10.1038/bjp.2008.175; published online 12 May 2008
British Journal of Pharmacology, 2009
Background and purpose: It has been demonstrated that cannabinoids evoke the release of endogenous opioids to produce antinociception; however, no information exists regarding the participation of cannabinoids in the antinociceptive mechanisms of opioids. The aim of the present study was to determine whether endocannabinoids are involved in central antinociception induced by activation of µ-, δ- and κ-opioid receptors.Experimental approach: Nociceptive threshold to thermal stimulation was measured according to the tail-flick test in Swiss mice. Morphine (5 µg), SNC80 (4 µg), bremazocine (4 µg), AM251 (2 and 4 µg), AM630 (2 and 4 µg) and MAFP (0.1 and 0.4 µg) were administered by the intracerebroventricular route.Key results: The CB1-selective cannabinoid receptor antagonist AM251 completely reversed the central antinociception induced by morphine in a dose-dependent manner. In contrast, the CB2-selective cannabinoid receptor antagonist AM630 did not antagonize this effect. Additionally, the administration of the anandamide amidase inhibitor, MAFP, significantly enhanced the antinociception induced by morphine. In contrast, the antinociceptive effects of δ- and κ-opioid receptor agonists were not affected by the cannabinoid antagonists. The antagonists alone caused no hyperalgesic or antinociceptive effects.Conclusions and implications: The results provide evidence for the involvement of cannabinoid CB1 receptors in the central antinociception induced by activation of µ-opioid receptors by the agonist morphine. The release of endocannabinoids appears not to be involved in central antinociception induced by activation of κ- and δ-opioid receptors.
2014
The management of chronic pain is one of the greatest challenges in modern medicine. Opiates such as morphine have been used to treat pain for centuries. However, the long term use of morphine is limited due to its side-effects. To date, a number of natural compounds have been detected to possess analgesic effects. One of these natural compound is mitragynine (MG) which is isolated from Mitragyna speciosa Korth. Mitragyna speciosa is popularly known as ‘ketum’ in Malaysia and ‘kratom’ in Thailand. Over 25 alkaloids are found in Mitragyna speciosa, MG being a major one. In this study, we investigated the action of MG as antinociceptive agent and the receptor selectivity effect. The nociceptive effect was estimated in a hot plate test (Ugo Basile model 7280; 50.0 oC). The latency time was estimated until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for every 15 minutes until 120 minutes. Male ICR mice (n=8/group) were admi...
European Journal of Pharmacology, 2005
Several recent reports have demonstrated a role for selective cannabinoid CB 2 receptor agonists in pain modulation, showing both analgesic and antihyperalgesic activities. While the mechanism of action is poorly understood, it has been postulated that these effects may be indirect, involving release of endogenous opioids. We have previously reported that administration of the selective cannabinoid CB 2 receptor agonist GW405833 (2,3-dichloro-phenyl)-[5-methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]-methanone) to rats elicits potent and efficacious antihyperalgesic effects against neuropathic and inflammatory pain and, at high dose (100 mg/kg), is analgesic and ataxic [Valenzano, K.Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 48, 658-672]. In the current study, we confirm these properties using mouse models and investigate the role of cannabinoid CB 2 receptors using knockout animals. Furthermore, we provide evidence that the antinociceptive properties of GW405833 are opioid independent. GW405833 elicited robust antihyperalgesic effects in mouse models of inflammatory (Freund's complete adjuvant) and neuropathic (Seltzer) pain. In contrast, GW405833 showed no antihyperalgesic activity against Freund's complete adjuvant-mediated inflammatory pain in cannabinoid CB 2 receptor knockout mice. As in rats, high-dose GW405833 (100 mg/kg) showed both analgesic and sedative activities in wild-type mice, activities that were also apparent in cannabinoid CB 2 receptor knockout mice. In rats, neither the antihyperalgesic effect in the Freund's complete adjuvant model nor the analgesic effects in tail flick and hot plate assays were inhibited by pre-treatment with the non-selective opioid receptor antagonist, naltrexone. These data demonstrate that the antihyperalgesic effects of GW405833 are mediated via the cannabinoid CB 2 receptor, whereas the analgesic and sedative effects are not. Furthermore, these data suggest that the mechanism of action for GW405833 does not depend on the release of endogenous opioids.
Involvement of cannabinoid receptors in peripheral and spinal morphine analgesia
Neuroscience, 2014
The interactions between the cannabinoid and opioid systems for pain modulation are reciprocal. However, the role and the importance of the cannabinoid system in the antinociceptive effects of opioids remain uncertain. We studied these interactions with the goal of highlighting the involvement of the cannabinoid system in morphineinduced analgesia. In both phases of the formalin test, intra paw and intrathecal morphine produced similar antinociceptive effects in C57BL/6, cannabinoid type 1 and type 2 receptor wild-type (respectively cnr1WT and cnr2WT) mice. In cnr1 and cnr2 knockout (KO) mice, at the dose used the antinociceptive effect of intra paw morphine in the inflammatory phase of the formalin test was decreased by 87% and 76%, respectively. Similarly, the antinociceptive effect of 0.1 lg spinal morphine in the inflammatory phase was abolished in cnr1KO mice and decreased by 90% in cnr2KO mice. Interestingly, the antinociceptive effect of morphine in the acute phase of the formalin test was only reduced in cnr1KO mice. Notably, systemic morphine administration produced similar analgesia in all genotypes, in both the formalin and the hot water immersion tail-flick tests. Because the pattern of expression of the mu opioid receptor (MOP), its binding properties and its G protein coupling remained unchanged across genotypes, it is unlikely that the loss of morphine analgesia in the cnr1KO and cnr2KO mice is the consequence of MOP malfunction or downregulation due to the absence of its heterodimerization with either the CB 1 or the CB 2 receptors, at least at the level of the spinal cord. Ó
Pain Practice, 2001
We have examined the effects of cannabinoid agonists on hyperalgesia in a model of neuropathic pain in the rat and investigated the possible sites of action. The antihyperalgesic activity of the cannabinoids was compared with their ability to elicit behavioural effects characteristic of central cannabinoid activity. WIN55,212-2 (0.3±10 mg kg 21 ), CP-55,940 (0.03±1 mg kg 21 ) and HU-210 (0.001±0.03 mg kg 21 ) were all active in a`tetrad' of tests consisting of tail-¯ick, catalepsy, rotarod and hypothermia following subcutaneous administration, with a rank order of potency in each of HU-210 . CP-55,940 . WIN55,212-2. The effects of WIN55,212-2 in each assay were blocked by the Cannabinoid 1 (CB 1 ) antagonist SR141716A. In the partial sciatic ligation model of neuropathic pain WIN55,212-2, CP-55,940 and HU-210 produced complete reversal of mechanical hyperalgesia within 3 h of subcutaneous administration with D 50 values of 0.52, 0.08 and 0.005 mg kg 21 , respectively. In this model WIN55,212-2 was also effective against thermal hyperalgesia and mechanical allodynia. WIN55,212-2 produced pronounced reversal of mechanical hyperalgesia following intrathecal administration that was blocked by the CB 1 antagonist SR141716A. Following intraplantar administration into the ipsilateral hindpaw, WIN55,212-2 produced up to 70% reversal of mechanical hyperalgesia, although activity was also observed at high doses following injection into the contralateral paw. The antihyperalgesic effect of WIN55,212-2 injected into the ipsilateral paw was blocked by subcutaneously administered SR141716A, but was not affected by intrathecally administered SR141716A. These data show that cannabinoids are highly potent and ef®cacious antihyperalgesic agents in a model of neuropathic pain. This activity is likely to be mediated via an action in both the CNS and in the periphery. q 2001 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved. Keywords: Central and peripheral Cannabinoid 1 receptors; Antihyperalgesic activity of cannabinoids; Model of neuropathic pain Pain 92 (2001) 91±100
CB 2 cannabinoid receptor mediation of antinociception
Pain, 2006
Management of acute pain remains a significant clinical problem. In preclinical studies, CB 2 cannabinoid receptor-selective agonists inhibit nociception without producing central nervous system side effects. The CB 2 receptor-selective agonist AM1241 produces antinociceptive effects that are antagonized by CB 2 , but not CB 1 , receptor-selective antagonists, suggesting that activation of CB 2 receptors results in antinociception. However, it has not been possible to definitively demonstrate that these effects are mediated by CB 2 receptors, because we have lacked the pharmacological tools to confirm the in vivo receptor selectivity of the antagonists used. Further, recent evidence for cannabinoid-like receptors beyond CB 1 and CB 2 raises the possibility that AM1241 exerts its antinociceptive effects at uncharacterized CB 2 -like receptors that are also inhibited by AM630. The experiments reported here further test the hypothesis that CB 2 receptor activation inhibits nociception. They evaluated the antinociceptive actions of AM1241 and the lessselective CB 2 receptor agonist WIN55,212-2 in wild-type ðCB þ=þ 2 Þ mice and in mice with genetic disruption of the CB 2 receptor (CB À=À 2 mice). AM1241 inhibited thermal nociception in CB þ=þ 2 mice, but had no effect in CB À=À 2 littermates. WIN55,212-2 produced equivalent antinociception in CB þ=þ 1 and CB À=À 1 mice, while its antinociceptive effects were reduced in CB À=À 2 compared to CB þ=þ 2 mice. The effects of morphine were not altered in CB À=À 2 compared to CB þ=þ 2 mice. These data strongly suggest that AM1241 produces antinociception in vivo by activating CB 2 cannabinoid receptors. Further, they confirm the potential therapeutic relevance of CB 2 cannabinoid receptors for the treatment of acute pain. Ó
Life Sciences, 2009
Aims: In this study, we investigated whether the opioid system and the nitric oxide pathway were involved in the peripheral antinociception induced by a cannabinoid receptor agonist anandamide. Main methods: Hyperalgesia was induced by a subcutaneous injection of carrageenan (250 μg) into the plantar surface of the rat's hindpaw and measured by the paw pressure test 3 h after injection. The weight in grams (g) required to elicit a nociceptive response, paw flexion, was determined as the nociceptive threshold. Key findings: Anandamide elicited a dose-dependent (50, 75, and 100 ng per paw) antinociceptive effect. The highest dose of anandamide did not produce antihyperalgesia in the contralateral paw, indicating a peripheral site of action. The CB 1 receptor antagonist AM251 (20, 40, 80 and 160 μg per paw) antagonized peripheral antihyperalgesia induced by anandamide (100 ng), in a dose-dependent manner, suggesting CB 1 receptor activation. Anandamide-induced peripheral antihyperalgesia was reverted by blockers of the L-arginine/NO/ cGMP pathway N G -nitro-L-arginine (NOARG; 24, 36 and 48 μg per paw) and 1H-[1,2,4] Oxadiazolo[4,3-a] quinoxalin-1-one (ODQ; 25, 50 and 100 μg per paw), in a dose-dependent manner. Furthermore, opioid receptor antagonist naloxone (12.5, 25 and 50 μg per paw) antagonized the peripheral antihyperalgesia induced by anandamide.