Effects of morphine/CP55940 mixtures on an impulsive choice task in rhesus monkeys

Abstract

µ-Opioid receptor agonists are commonly used to treat pain despite their adverse effects. In preclinical studies, cannabinoid receptor agonists increase the potency of opioids for producing antinociceptive but not reinforcing effects. It is unknown whether other adverse effects of these drugs, such as impairment of complex behavior, are enhanced by their co-administration. This study characterized the effects of morphine (µ-opioid receptor agonist; 0.32-5.6 mg/kg, subcutaneously) and CP55940 (CB1/CB2 cannabinoid receptor agonist; 0.0032-0.32 mg/kg, subcutaneously), alone and in mixtures, in monkeys (n=3) choosing between one pellet delivered immediately and two pellets delivered after a delay. Two consecutive choices of the immediate or delayed reward decreased or increased, respectively, the delay. The median adjusted delay, indicating indifference between the immediate and delayed reinforcers, was increased by morphine (3.2 mg/kg) and CP55940 (0.01-0.032 mg/kg). Performance after administration of morphine (0.32 and 1 mg/kg)/CP55940 (0.0032-0.032 mg/kg) mixtures was not different from performance after CP55940 alone. Neither morphine, CP55940, nor mixtures decreased the median adjusted delay (i.e. increased impulsivity). These findings failed to confirm previous studies showing that morphine increases impulsivity, perhaps because of procedural differences among studies. Treatment of pain often requires repeated drug administration; thus, it remains to be determined whether the present findings predict the effects of chronically administered morphine/CP5540 mixtures on impulsive choice.

Antinociceptive and Abuse Potential Effects of Cannabinoid/Opioid Combinations in a Chronic Pain Model in Rats

“…In addition, other CB1 agonists produced similar effects in ICSS such as Δ9-tetrahydrocannabinol and WIN55,212-2 ((R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate) [31,46]. This depression in ICSS can possibly be attributed to their sedative effect at high doses [7]. On the other hand, morphine’s effect on ICSS has been adequately studied and showed a variable action of increasing and decreasing ICSS at low doses and high doses, respectively [2,47,48].…”

“…Cannabinoid signaling is largely involved in the regulation of nociception, representing a fundamental target for pharmacological intervention [3,6]. Most cannabinoid receptor ligands such as CP55940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl) -phenol) act preferentially through the activation of the cannabinoid receptor 1 (CB1) receptor [7]. The activation of CB1 produced antinociceptive effects in several laboratory species using several methods to analyze pain sensitivity in both acute and chronic pain models [6,8,9].…”

“…Pharmacological additive or synergistic approaches have been utilized to enhance the analgesic effects of several compounds, especially when using lower doses can lower the risk of undesirable side effects [7]. In this context, the opioid and cannabinoid antinociceptive systems largely overlap.…”