Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat

Cox, Melinda L.; Haller, Victoria L.; Welch, Sandra P.

doi:10.1016/j.ejphar.2007.04.010

Cited by 71 publications

(68 citation statements)

References 26 publications

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“…Specifically, the combination of THC and morphine produced synergistic antinociceptive effects in the rat complete Freund's adjuvant model of arthritis (Cox et al, 2007). Likewise, compared with opioid treatment only, chronic pain patients treated with both cannabis and opioids reported feeling less pain (Abrams et al, 2011).…”

Section: Discussionmentioning

confidence: 97%

“…In current times, preclinical studies have established that the combination of opiates and cannabinoids produce enhanced antinociceptive effects. Coadministration of the primary psychoactive component of marijuana, D 9 -tetrahydrocannabinol (THC) (Gaoni and Mechoulam, 1964), and morphine produces synergistic antinociceptive effects in acute pain tests (Cichewicz and Welch, 2003) and in the rat Freund's complete adjuvantinduced arthritic model (Cox et al, 2007). Additionally, the potent synthetic cannabinoid receptor agonist CP55,940 produces a leftward shift of the morphine dose response curve in the acetic acid abdominal stretching pain assay (Miller et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Wilkerson

Niphakis

Grim

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Serious clinical liabilities associated with the prescription of opiates for pain control include constipation, respiratory depression, pruritus, tolerance, abuse, and addiction. A recognized strategy to circumvent these side effects is to combine opioids with other antinociceptive agents. The combination of opiates with the primary active constituent of cannabis (D 9 -tetrahydrocannabinol) produces enhanced antinociceptive actions, suggesting that cannabinoid receptor agonists can be opioid sparing. Here, we tested whether elevating the endogenous cannabinoid 2-arachidonoylglycerol through the inhibition of its primary hydrolytic enzyme monoacylglycerol lipase (MAGL), will produce opioid-sparing effects in the mouse chronic constriction injury (CCI) of the sciatic nerve model of neuropathic pain. The dose-response relationships of i.p. administration of morphine and the selective MAGL inhibitor 2,5-dioxopyrrolidin-1-yl 4-(bis (4-chlorophenyl)methyl)piperazine-1-carboxylate (MJN110) were tested alone and in combination at equieffective doses for reversal of CCI-induced mechanical allodynia and thermal hyperalgesia. The respective ED 50 doses (95% confidence interval) of morphine and MJN110 were 2.4 (1.9-3.0) mg/kg and 0.43 (0.23-0.79) mg/kg. Isobolographic analysis of these drugs in combination revealed synergistic antiallodynic effects. Acute antinociceptive effects of the combination of morphine and MJN110 required m-opioid, CB 1 , and CB 2 receptors. This combination did not reduce gastric motility or produce subjective cannabimimetic effects in the drug discrimination assay. Importantly, combinations of MJN110 and morphine given repeatedly (i.e., twice a day for 6 days) continued to produce antiallodynic effects with no evidence of tolerance. Taken together, these findings suggest that MAGL inhibition produces opiate-sparing events with diminished tolerance, constipation, and cannabimimetic side effects.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Wilkerson

Niphakis

Grim

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…-HU-210 and the non-steroidal anti-inflammatory drug, acetylsalicylic acid, co-administered systemically, in the rat hot plate model of acute pain [76]; -D 9 -THC and an opioid such as morphine, codeine or fentanyl in mouse, rat, guinea pig and monkey models of acute or arthritic pain [79][80][81][82][83][84][85][86][87][88][89]; -CP55940 and the a 2 -adrenoceptor agonist, dexmedetomidine, in the mouse hot plate and tail flick models of acute pain [83]; -CP55940 and the N-methyl-D-aspartate (NMDA) receptor antagonist, (-)-6-phosphonomethyl-decahydroisoquinoline-3-carboxylic acid (LY235959), in the mouse hot plate test [90]; and -R-(þ)-WIN55212, given by intracerebroventricular or intraplantar injection, and a selective agonist for the neuropeptide FF 1 or FF 2 receptor, injected intracerebroventricularly, in mouse models of acute pain [91].…”

Section: Potential Adjunctive Strategies For Cannabinoid Receptor Actmentioning

confidence: 99%

“…Importantly, evidence has been obtained through the construction of isobolograms that of the above interactions, those between R-(þ)-WIN55212 and clonidine, neostigmine or bupivicaine [73,74] as well as those between anandamide and ibuprofen [75], D 9 -THC and an opioid [81,83,86], CP55940 and dexmedetomidine [83] and CP55940 and LY235959 [90], are all synergistic rather than just additive in nature. A synergistic antinociceptive interaction has also been reported to occur between the CB 1 -selective agonist, arachidonylcyclopropylamide, and the CB 2 -selective agonist, AM1241, in a mouse model of cancer pain following intraplantar coadministration of these two compounds [22].…”

Section: Potential Adjunctive Strategies For Cannabinoid Receptor Actmentioning

confidence: 99%

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

Pertwee

2012

Phil. Trans. R. Soc. B

311

269

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Human tissues express cannabinoid CB 1 and CB 2 receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB 1 /CB 2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; D 9 -tetrahydrocannabinol (D 9 -THC)) and Sativex (D 9 -THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB 2 receptors, and/or (v) adjunctive 'multi-targeting'.

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“…51 Moreover, cannabinoids are increasingly being recognized in animal models for their potential sparing effects with opioids 52 of neuropathic pain and arthritic pain. 53 Although similar effects have not been translated to human studies, Robert et al 54 found a synergistic affective analgesia between ⌬9-THC and morphine in experimentally induced pain in human volunteers.…”

Section: Analgesic Potential and Synergism With Opioidsmentioning

confidence: 99%

Cannabis and Its Derivatives: Review of Medical Use

Leung

2011

The Journal of the American Board of Family Medicine

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Background: Use of cannabis is often an under-reported activity in our society. Despite legal restriction, cannabis is often used to relieve chronic and neuropathic pain, and it carries psychotropic and physical adverse effects with a propensity for addiction. This article aims to update the current knowledge and evidence of using cannabis and its derivatives with a view to the sociolegal context and perspectives for future research.Methods: Cannabis use can be traced back to ancient cultures and still continues in our present society despite legal curtailment. The active ingredient, ⌬9-tetrahydrocannabinol, accounts for both the physical and psychotropic effects of cannabis. Though clinical trials demonstrate benefits in alleviating chronic and neuropathic pain, there is also significant potential physical and psychotropic side-effects of cannabis. Recent laboratory data highlight synergistic interactions between cannabinoid and opioid receptors, with potential reduction of drug-seeking behavior and opiate sparing effects. Legal rulings also have changed in certain American states, which may lead to wider use of cannabis among eligible persons.

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Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat

Cited by 71 publications

References 26 publications

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

The Selective Monoacylglycerol Lipase Inhibitor MJN110 Produces Opioid-Sparing Effects in a Mouse Neuropathic Pain Model

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

Cannabis and Its Derivatives: Review of Medical Use

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