The μ‐opioid receptor agonist morphine, but not agonists at δ‐ or κ‐opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors

Pacheco, Daniela da Fonseca; Klein, André; Perez, Andrea de Castro; Pacheco, Cinthia Mara da Fonseca; Francischi, Janetti Nogueira de; Duarte, I.D.G.

doi:10.1038/bjp.2008.175

Cited by 75 publications

(50 citation statements)

References 52 publications

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“…Recent evidence suggests a role of MCP-1/CCL2 in opioid tolerance (Zhao et al, 2012). Given that m-opioid and cannabinoid receptors are widely expressed in both the CNS and periphery, it is important to note that the observed behavioral effects may be due to receptor function at the peripheral nociceptors (Desroches et al, 2014), dorsal root ganglia (Khasabova et al, 2004), dorsal horn of the spinal cord (da Fonseca Pacheco et al, 2008;Desroches et al, 2014), and periaqueductal gray and other brain regions (Páldy et al, 2008;Wilson-Poe et al, 2015) implicated in the regulation of nociception. CB 1 and CB 2 receptors appeared to play a differential role in mediating the antinociceptive effects of morphine and MJN110 given in combination.…”

Section: Discussionmentioning

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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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: 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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“…Fatty acid amide hydrolase associations with opioid outcomes Research Article vice versa [40]. In fact, CB agonists enhance the effect of μ-opioid receptor agonists in a variety of models of analgesia [41].…”

Section: Discussionmentioning

confidence: 99%

Fatty Acid Amide Hydrolase–morphine Interaction Influences Ventilatory Response to Hypercapnia and Postoperative Opioid Outcomes in Children

et al. 2016

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Aim: Fatty acid amide hydrolase (FAAH) degrades anandamide, an endogenous cannabinoid. We hypothesized that FAAH variants will predict risk of morphine-related adverse outcomes due to opioid-endocannabinoid interactions. Patients & methods:In 101 postsurgical adolescents receiving morphine analgesia, we prospectively studied ventilatory response to 5% CO 2 (HCVR), respiratory depression (RD) and vomiting. Blood was collected for genotyping and morphine pharmacokinetics. Results: We found significant FAAH-morphine interaction for missense (rs324420) and several regulatory variants, with HCVR (p < 0.0001) and vomiting (p = 0.0339). HCVR was more depressed in patients who developed RD compared with those who did not (p = 0.0034), thus FAAH-HCVR association predicts risk of impending RD from morphine use. Conclusion: FAAH genotypes predict risk for morphine-related adverse outcomes.

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“…Previous studies have examined interactions between the cannabinoid and opioid systems by administering CB1 agonists in combination with morphine and have consistently shown that CB1 agonists enhance the antinociceptive effects of morphine (Smith and Martin, 1992;Welch and Stevens, 1992;Smith et al, 1994;Welch et al, 1995;Massi et al, 2001). More recent studies using CB1 antagonists also provide evidence that endogenous cannabinoids mediate the antinociceptive effects of morphine (da Fonseca Pacheco et al, 2008;Pacheco et al, 2009;Miller et al, 2011). Moreover, morphine's antinociceptive effects are enhanced when AEA is protected from metabolism (da Fonseca Pacheco et al, 2008;Haller et al, 2008;Pacheco et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…For example, CB1 antagonists attenuate morphine-induced antinociception in the hotplate, writhing, and tail-flick tests (Pacheco et al, 2009;Miller et al, 2011) and in models of hyperalgesia (da Fonseca Pacheco et al, 2008). Exogenously administered AEA in combination with the FAAH inhibitor cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3-yl ester (URB597), N-(4-hydroxyphenyl)arachidonylamide (AM404) enhances the antinociceptive effects of morphine in the tail-flick test (Haller et al, 2008), and methylarachidonoylflurophosphate, which inhibits the degradation of the endogenous cannabinoids AEA and 2-arachidonoylethanolamine, enhances the antinociceptive effects of morphine in the tail-flick test and in hyperalgesia models (da Fonseca Pacheco et al, 2008;Pacheco et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Effects of Alterations in Cannabinoid Signaling, Alone and in Combination with Morphine, on Pain-Elicited and Pain-Suppressed Behavior in Mice

Miller¹,

Picker²,

Umberger³

et al. 2012

J Pharmacol Exp Ther

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Inhibitors of fatty acid amide hydrolase (FAAH) and anandamide (AEA) uptake, which limit the degradation of endogenous cannabinoids, have received interest as potential therapeutics for pain. There is also evidence that endogenous cannabinoids mediate the antinociceptive effects of opioids. Assays of pain-elicited and pain-suppressed behavior have been used to differentiate the effects of drugs that specifically alter nociception from drugs that alter nociception caused by nonspecific effects such as catalepsy or a general suppression of activity. Using such procedures, this study examines the effects of the direct cannabinoid type 1 (CB1) agonist (Ϫ)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55940), the FAAH inhibitor cyclohexylcarbamic acid 3Ј-carbamoylbiphenyl-3-yl ester (URB597), and the AEA uptake inhibitor N-(4-hydroxyphenyl) arachidonylamide (AM404). Additional experiments examined these compounds in combination with morphine. CP55940 produced antinociception in assays of pain-elicited, but not pain-suppressed, behavior and disrupted responding in an assay of schedule-controlled behavior. URB597 and AM404 produced antinociception in assays of pain-elicited and painsuppressed behavior in which acetic acid was the noxious stimulus, but had no effect on the hotplate and schedulecontrolled responding. CP55940 in combination with morphine resulted in effects greater than those of morphine alone in assays of pain-elicited and scheduled-controlled behavior but not pain-suppressed behavior. URB597 in combination with morphine resulted in enhanced morphine effects in assays of pain-elicited and pain-suppressed behavior in which diluted acetic acid was the noxious stimulus, but did not alter morphine's effects on the hotplate or schedule-controlled responding. These studies suggest that, compared with direct CB1 agonists, manipulations of endogenous cannabinoid signaling have enhanced clinical potential; however, their effects depend on the type of noxious stimulus.

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The μ‐opioid receptor agonist morphine, but not agonists at δ‐ or κ‐opioid receptors, induces peripheral antinociception mediated by cannabinoid receptors

Cited by 75 publications

References 52 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

Fatty Acid Amide Hydrolase–morphine Interaction Influences Ventilatory Response to Hypercapnia and Postoperative Opioid Outcomes in Children

Effects of Alterations in Cannabinoid Signaling, Alone and in Combination with Morphine, on Pain-Elicited and Pain-Suppressed Behavior in Mice

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