Interactions between<i>μ</i>-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

Maguire, David R.; Yang, Wuyi

doi:10.1124/jpet.113.204099

Cited by 70 publications

(87 citation statements)

References 45 publications

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“…Portions of this manuscript were presented at the 2016 annual meetings Experimental Biology and American Society for Pharmacology and Experimental Therapeutics in San Diego, CA, and Behavior, Biology, agonists (Maguire et al, 2013). If adverse effects are not apparent at smaller doses, then k opioid/cannabinoid mixtures could be useful for treating pain and might be preferred to m opioid receptor agonists.…”

Section: Introductionmentioning

confidence: 99%

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

Minervini¹,

Dahal²,

France³

2016

J Pharmacol Exp Ther

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Pain is a significant clinical problem, and there is a need for more effective treatments with reduced adverse effects that currently limit the use of m opioid receptor agonists. Synthetic k opioid receptor agonists have no abuse liability and well-documented antinociceptive effects; however, adverse effects (diuresis, dysphoria) preclude their use in the clinic. Combining k opioids with nonopioid drugs (cannabinoid receptor agonists) allows for smaller doses of each drug to produce antinociception. This study tested whether a potentially useful effect of the k opioid receptor agonist 2-Cumulative dose-response functions were determined in eight male Sprague-Dawley rats for spiradoline (0.032-32.0 mg/kg, i.p.) and CP55940 (0.0032-1.0 mg/kg, i.p.) for antinociception, hypothermia, food-maintained responding, and diuresis. Alone, each drug dose dependently increased tail withdrawal latencies from 50°C water, decreased body temperature by ∼4°C, and eliminated food-maintained responding. Spiradoline, but not CP55940, significantly increased urine output at doses that eliminated responding. Smaller doses of spiradoline and CP55940 in mixtures (3:1, 1:1, and 1:3 spiradoline:CP55940) had effects comparable to those observed with larger doses of either drug administered alone: the interaction was additive for antinociception and additive or greater than additive for hypothermia and food-maintained responding. Collectively, these data fail to provide support for the use of these mixtures for treating acute pain; however, k opioid/cannabinoid mixtures might be useful for treating pain under other conditions (e.g., chronic pain), but only if the adverse effects of both drugs are not enhanced in mixtures.

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Section: Introductionmentioning

confidence: 99%

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

Minervini¹,

Dahal²,

France³

2016

J Pharmacol Exp Ther

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“…Combining cannabinoids with other drugs that have analgesic effects (e.g., opioids) appears to be a promising approach to treat pain. Cannabinoid receptor agonists enhance the antinociceptive effects of m-opioid receptor agonists in rodents (Welch and Stevens, 1992;Finn et al, 2004) and nonhuman primates (Li et al, 2008;Maguire et al, 2013). Moreover, cannabinoid receptor agonists, taken orally or through inhalation of vaporized or smoked marijuana, enhance the analgesic effects of opioids in patients (Lynch and Clark, 2003;Narang et al, 2008;Abrams et al, 2011;Johnson et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In nonhuman primates, cannabinoid receptor agonists markedly enhanced the antinociceptive effects of morphine (Li et al, 2008;Maguire et al, 2013); however, combinations with opioids that have different pharmacologic properties (e.g., different intrinsic efficacy) might offer better therapeutic outcomes by maximizing pain relief and minimizing unwanted effects. For example, some lower efficacy m-opioid receptor agonists (e.g., nalbuphine) have fewer and less severe adverse effects, such as respiratory depression, compared with higher efficacy agonists (Liguori et al, 1996;Dahan et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Impact of Efficacy at theμ-Opioid Receptor on Antinociceptive Effects of Combinations ofμ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

Maguire

2014

J Pharmacol Exp Ther

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Cannabinoid receptor agonists, such as D 9-tetrahydrocannabinol (D 9 -THC), enhance the antinociceptive effects of m-opioid receptor agonists, which suggests that combining cannabinoids with opioids would improve pain treatment. Combinations with lower efficacy agonists might be preferred and could avoid adverse effects associated with large doses; however, it is unclear whether interactions between opioids and cannabinoids vary across drugs with different efficacy. The antinociceptive effects of m-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n 5 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, D 9 -THC, and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol) each increased tail withdrawal latency. Pretreatment with doses of D 9 -THC (1.0 mg/kg) or CP 55,940 (0.032 mg/kg) that were ineffective alone shifted the fentanyl dose-effect curve leftward 20.6-and 52.9-fold, respectively, and the etorphine dose-effect curve leftward 12.4-and 19.6-fold, respectively. D 9-THC and CP 55,940 shifted the morphine dose-effect curve leftward only 3.4-and 7.9-fold, respectively, and the buprenorphine curve only 5.4-and 4.1-fold, respectively. Neither D 9-THC nor CP 55,940 significantly altered the effects of nalbuphine. Cannabinoid receptor agonists increase the antinociceptive potency of higher efficacy opioid receptor agonists more than lower efficacy agonists; however, because much smaller doses of each drug can be administered in combinations while achieving adequate pain relief and that other (e.g., abuse-related) effects of opioids do not appear to be enhanced by cannabinoids, these results provide additional support for combining opioids with cannabinoids to treat pain.

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“…Interactions between cannabinoids and k-opioids have been explored previously, based on their common signaling transduction mechanisms or their often similar behavioral effects (Hampson et al, 2000;Walentiny et al, 2010;Maguire et al, 2014). For example, the k-opioid antagonist nor-binaltorphimine will block the antinociceptive effects of THC, whereas coadministration of cannabinoid and k-opioid agonists has additive antinociceptive effects (Smith et al, 1994;Maguire and France, 2016).…”

Section: Discussionmentioning

confidence: 99%

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

Chopda

Parge

Thakur

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Daily treatment with cannabinoids results in tolerance to many, but not all, of their behavioral and physiologic effects. The present studies investigated the effects of 7-day exposure to 10 mg/kg daily of D 9-tetrahydrocannabinol (THC) on the diuretic and antinociceptive effects of THC and the synthetic cannabinoid AM4054. Comparison studies determined diuretic responses to the k-opioid agonist U50,488 and furosemide. After determination of control dose-response functions, mice received 10 mg/kg daily of THC for 7 days, and dose-response functions were re-determined 24 hours, 7 days, or 14 days later. THC and AM4054 had biphasic diuretic effects under control conditions with maximum effects of 30 and 35 ml/kg of urine, respectively. In contrast, antinociceptive effects of both drugs increased monotonically with dose to .90% of maximal possible effect. Treatment with THC produced 9-and 7-fold rightward shifts of the diuresis and antinociception doseresponse curves for THC and, respectively, 7-and 3-fold rightward shifts in the AM4054 dose-response functions. U50,488 and furosemide increased urine output to .35 ml/kg under control conditions. The effects of U50,488 were attenuated after 7-day treatment with THC, whereas the effects of furosemide were unaltered. Diuretic effects of THC and AM4054 recovered to near-baseline levels within 14 days after stopping daily THC injections, whereas tolerance to the antinociceptive effects persisted longer than 14 days. The tolerance induced by 7-day treatment with THC was accompanied by a 55% decrease in the B max value for cannabinoid receptors (CB1). These data indicate that repeated exposure to THC produces similar rightward shifts in the ascending and descending limbs of cannabinoid diuresis doseeffect curves and to antinociceptive effects while resulting in a flattening of the U50,488 diuresis dose-effect function.

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Interactions betweenμ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists in Rhesus Monkeys: Antinociception, Drug Discrimination, and Drug Self-Administration

Cited by 70 publications

References 45 publications

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

Behavioral Characterization of κ Opioid Receptor Agonist Spiradoline and Cannabinoid Receptor Agonist CP55940 Mixtures in Rats

Impact of Efficacy at theμ-Opioid Receptor on Antinociceptive Effects of Combinations ofμ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

Tolerance to the Diuretic Effects of Cannabinoids and Cross-Tolerance to a -Opioid Agonist in THC-Treated Mice

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