Effects of Morphine/CP55940 Mixtures on an Impulsive Choice Task in Rhesus Monkeys
Authors: Minervini Vanessa , France Charles P. 
Published: November 2023

Pain is the leading reason for seeking medical care. Mu opioid receptor agonists are commonly prescribed to treat moderate to severe pain despite adverse effects such as respiratory depression, abuse, and constipation. In animal models of pain, cannabinoid receptor agonists increase the potency of opioids to produce antinociception at doses that do not increase the potency of opioids to produce reinforcing effects. It is unknown whether cannabinoids enhance other adverse effects of opioids. Opioids and cannabinoids can impair cognition in humans; this study used an impulsive choice task (delay discounting) to characterize the effects of the mu opioid receptor agonist morphine (0.32 – 5.6 mg/kg, s.c.), the cannabinoid receptor agonist CP55940 (0.0032 – 0.32 mg/kg, s.c.), and morphine/CP55940 mixtures in three adult male rhesus monkeys. Monkeys chose between 1 pellet delivered immediately and 2 pellets delivered after a delay. The delay adjusted within‐session based on performance: two consecutive choices of the immediate or delayed reward decreased or increased, respectively, the delay by 25%. Pretreatment times were 15 min for morphine and 60 min for CP55940. Under control conditions, the median adjusted delay, indicating indifference between 1 immediate pellet and 2 delayed pellets, was 33, 44, and 101 sec for individual monkeys. Morphine had no effect on median adjusted delay in two subjects up to doses that decreased responding; however, for one subject morphine dose‐dependently increased the median adjusted delay (i.e., decreasing discounting) and caused exclusive choice for the larger delayed reward. CP55940 produced an inverted U‐shaped dose‐response function with at least one dose significantly increasing the median adjusted delay in each monkey. In two monkeys, 0.01 mg/kg CP55940 increased the median adjusted delay from 33 and 101 sec to 73 and 173 sec, respectively. In the third monkey, 0.032 mg/kg CP55940 increased the median adjusted delay from 44 to 83 sec. Potency differences for CP55940 among individuals were not related to baseline delays. When 0.32 and 1 mg/kg morphine were tested in combination with CP55940 (0.0032 – 0.032 mg/kg), the effects on performance were not different from the effects of CP55940 alone. Conversely, doses of morphine and CP55940 that individually were without effect on response rate decreased responding by at least 50% when tested in combination. Overall, neither morphine nor CP55940 decreased the adjusted delay (i.e., increased discounting) in this task, and the effects of CP55940/morphine mixtures on response rate but not adjusted delay were greater than the effects of either drug alone. These results extend previous work showing that cannabinoids enhance antinociceptive effects but not adverse (reinforcing) effects of opioids. Because treatment of pain often requires repeated drug administration, the effects of morphine/CP5540 mixtures on cognitive performance need to be assessed during and after daily drug administration.Support or Funding InformationThis work was supported by the National Institute on Drug Abuse grants R01DA029254, T32DA031115, and K05DA017918, and the Welch Foundation Grant AQ‐0039.