David R. Maguire

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

Cannabinoid receptor agonists enhance the antinociceptive effects of μ-opioid receptor agonists, which suggests that combinations of these drugs might enhance therapeutic effectiveness (e.g., analgesia). However, it is not clear whether combinations of these drugs also enhance abuse or dependence liability. This experiment examined whether combinations of cannabinoids and opioids that enhance antinociception also increase abuse-related effects by studying the effects of the cannabinoid receptor agonists 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol (CP 55,940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212) on the antinociceptive, discriminative stimulus, and positive reinforcing effects of μ-opioid receptor agonists in rhesus monkeys. In one group of monkeys (n = 3), morphine (0.1–5.6 mg/kg s.c.), CP 55,940 (0.0032–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) dose-dependently increased tail withdrawal latency from 50°C water, and pretreatment with small, otherwise ineffective, doses of CP 55,940 and WIN 55,212 shifted the morphine dose-effect curve to the left. In monkeys (n = 3) discriminating 3.2 mg/kg morphine, CP 55,940 (0.01–0.032 mg/kg s.c.) and WIN 55,212 (0.1–1.78 mg/kg s.c.) attenuated the discriminative stimulus effects of morphine, shifting the dose-effect curve to the right. In monkeys (n = 4) self-administering heroin (0.32–32.0 µg/kg/infusion i.v.), CP 55,940 (0.001–0.032 mg/kg s.c.), and WIN 55,212 (0.1–1.0 mg/kg s.c.) shifted the heroin dose-effect curve rightward and downward. Cannabinoid receptor agonists CP 55,940 and WIN 55,212 enhanced the antinociceptive effects but not the discriminative stimulus or positive reinforcing effects of μ-opioid receptor agonists in rhesus monkeys, supporting the view that combining cannabinoid and opioid receptor agonists might result in enhanced treatment effectiveness for pain without similarly enhancing abuse and dependence liability.

Impact of Efficacy at the μ-Opioid Receptor on Antinociceptive Effects of Combinations of μ-Opioid Receptor Agonists and Cannabinoid Receptor Agonists

Cannabinoid receptor agonists, such as Δ9-tetrahydrocannabinol (Δ9-THC), enhance the antinociceptive effects of μ-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 μ-opioid receptor agonists alone and in combination with cannabinoid receptor agonists were studied in rhesus monkeys (n = 4) using a warm water tail withdrawal procedure. Etorphine, fentanyl, morphine, buprenorphine, nalbuphine, Δ9-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 Δ9-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. Δ9-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 Δ9-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.

Determinants of choice, and vulnerability and recovery in addiction

Addiction may be viewed as choice governed by competing contingencies. One factor impacting choice, particularly as it relates to addiction, is sensitivity to delayed rewards. Discounting of delayed rewards influences addiction vulnerability because of competition between relatively immediate gains of drug use, e.g. intoxication, versus relatively remote gains of abstinence, e.g. family stability. Factors modifying delay sensitivity can be modeled in the laboratory. For instance, increased delay sensitivity can be similarly observed in adolescent humans and non-human animals. Similarly, genetic factors influence delay sensitivity in humans and animals. Recovery from addiction may also be viewed as choice behavior. Thus, reinforcing alternative behavior facilitates recovery because reinforcing alternative behavior decreases the frequency of using drugs. How reinforcing alternative behavior influences recovery can also be modeled in the laboratory. For instance, relapse risk decreases as abstinence duration increases, and this decreasing risk can be modeled in animals using choice procedures. In summary, addiction in many respects can be conceptualized as a problem of choice. Animal models of choice disorders stand to increase our understanding of the core processes that establish and maintain addiction and serve as a proving ground for development of novel treatments.

Effect of Delay on Self-Administration of Remifentanil under a Drug Versus Drug Choice Procedure in Rhesus Monkeys

Drug abuse can be conceptualized as excessive choice of drug over other reinforcers, and factors that affect drug taking can be examined experimentally using choice procedures. This study examined the impact of reinforcer delay on self-administration of the μ-opioid receptor agonist remifentanil in rhesus monkeys (n = 4) lever pressing under a concurrent fixed-ratio 30 schedule. Responding on either lever delivered an intravenous infusion of either remifentanil or saline. Dose-effect curves were first determined when responding on one lever delivered remifentanil and responding on a second lever delivered saline. Monkeys then chose between two doses of remifentanil, and delay to delivery of the large dose was varied systematically. Responding for remifentanil (0.01–1.0 µg/kg/infusion) increased dose-dependently when the alternative was saline or a dose of remifentanil. Delaying delivery of the large dose of remifentanil by 30, 60, 120, or 240 seconds increased responding for smaller, immediately available doses (0.01–0.1 µg/kg/infusion) and, in some cases, increased responding for doses of remifentanil that did not maintain responding when the alternative was saline. These data demonstrate that delaying the delivery of an opioid receptor agonist can significantly affect its reinforcing effectiveness. The imposition of a delay reduces the effectiveness of large doses of drug to maintain responding and increases the effectiveness of immediately available commodities, including smaller doses of drug. Increased reinforcing effectiveness of smaller doses of drug in the context of other delayed reinforcers might contribute to the development and maintenance of opioid abuse.

Impulsivity and drugs of abuse: a juice-reinforced operant procedure for determining within-session delay discounting functions in rhesus monkeys.

INTRODUCTION Impulsivity is a behavioral trait that is thought to contribute to a variety of disorders, including drug abuse. Efficient, sensitive procedures are needed for studying drug effects on impulsivity (e.g., delay discounting) in nonhumans. METHODS Three monkeys responded under an operant choice procedure whereby responses on one lever resulted in immediate delivery of 0.15 ml of juice [Hawaiian Punch®] and responses on another lever resulted in delivery of 0.75 ml of juice, either immediately or after a delay (3.75-40 s). The delay to the larger reinforcer increased within-session across discrete blocks allowing for generation of delay-discounting functions within sessions. RESULTS Without delay, monkeys chose the larger reinforcer nearly exclusively. With increasing delay, monkeys progressively switched their choice from the larger to the smaller reinforcer in a delay-dependent manner. In 2 monkeys, acute administration of morphine (0.1 and 0.32 mg/kg) or ketamine (0.1 and 0.32 mg/kg) but not diazepam (0.1-1.0 mg/kg) dose-dependently shifted the delay-discounting functions to the left, indicating increased discounting. In one monkey, daily morphine treatment (0.32 mg/kg/day, 3-hour pretreatment) produced a rapid, sustained leftward shift in the delay-discounting function; the curve returned to the pre-drug position 6 days after discontinuation of treatment. DISCUSSION This delay discounting procedure is sensitive to both behavioral and pharmacological manipulations and appears to be particularly sensitive to chronic drug treatment and drug withdrawal. Given the importance of drug dependence and withdrawal in the initiation, maintenance of, and relapse to drug taking, this procedure should be useful to study one aspect of this process.

Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl

Cannabinoid receptor agonists such as delta-9-tetrahydrocannabinol (Δ(9)-THC) enhance some (antinociceptive) but not other (positive reinforcing) effects of mu opioid receptor agonists, suggesting that cannabinoids might be combined with opioids to treat pain without increasing, and possibly decreasing, abuse. The degree to which cannabinoids enhance antinociceptive effects of opioids varies across drugs insofar as Δ(9)-THC and the synthetic cannabinoid receptor agonist CP55940 increase the potency of some mu opioid receptor agonists (e.g., fentanyl) more than others (e.g., nalbuphine). It is not known whether interactions between cannabinoids and opioids vary similarly for other (abuse-related) effects. This study examined whether Δ(9)-THC and CP55940 differentially impact the discriminative stimulus effects of fentanyl and nalbuphine in monkeys (n=4) discriminating 0.01mg/kg of fentanyl (s.c.) from saline. Fentanyl (0.00178-0.0178mg/kg) and nalbuphine (0.01-0.32mg/kg) dose-dependently increased drug-lever responding. Neither Δ(9)-THC (0.032-1.0mg/kg) nor CP55940 (0.0032-0.032mg/kg) enhanced the discriminative stimulus effects of fentanyl or nalbuphine; however, doses of Δ(9)-THC and CP55940 that shifted the nalbuphine dose-effect curve markedly to the right and/or down were less effective or ineffective in shifting the fentanyl dose-effect curve. The mu opioid receptor antagonist naltrexone (0.032mg/kg) attenuated the discriminative stimulus effects of fentanyl and nalbuphine similarly. These data indicate that the discriminative stimulus effects of nalbuphine are more sensitive to attenuation by cannabinoids than those of fentanyl. That the discriminative stimulus effects of some opioids are more susceptible to modification by drugs from other classes has implications for developing maximally effective therapeutic drug mixtures with reduced abuse liability.

Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys

Opioid abuse remains a significant public health problem; together with the greater availability of marijuana in some regions there is an increasing likelihood that opioids and marijuana will be used together. Polydrug abuse is associated with increased toxicity and poorer treatment outcome; thus, a better understanding of the consequences of repeated coadministration of these drugs will facilitate the development of better prevention and treatment strategies. This study examined the effects of daily treatment with the cannabinoid receptor agonist delta-9-tetrahydrocannabinol (&Dgr;9-THC) and its discontinuation on self-administration of heroin in rhesus monkeys (n=4) lever-pressing under a fixed-ratio 30 schedule. Heroin self-administration (0.32–32 &mgr;g/kg/infusion, intravenously) generated an inverted U-shaped dose–effect curve. Administered acutely, &Dgr;9-THC (0.01–0.32 mg/kg, subcutaneously) dose dependently decreased responding for heroin and flattened the self-administration dose–effect curve. Daily treatment with &Dgr;9-THC (0.01–0.1 mg/kg/12 h, subcutaneously) either had no effect on or decreased responding for heroin. In addition, daily treatment did not significantly impact extinction of heroin self-administration or resumption of responding for heroin after extinction. Discontinuation of daily &Dgr;9-THC treatment did not systematically impact rates of heroin self-administration. These data suggest that repeated administration of a cannabinoid receptor agonist likely does not increase, and possibly decreases, the positive reinforcing effects of a mu opioid receptor agonist.

Delay discounting of the μ-opioid receptor agonist remifentanil in rhesus monkeys.

Although increased impulsivity (delay discounting) is an important risk factor for drug abuse, the impact of delay on drug taking has received relatively little attention. This study examined delay discounting of the &mgr;-opioid receptor agonist remifentanil in rhesus monkeys (n=4) responding for intravenous infusions under a concurrent choice procedure. Dose–effect curves for remifentanil were determined by varying the dose available on one lever (0.001–0.32 &mgr;g/kg/infusion) while keeping the dose available on the other lever (0.1 &mgr;g/kg/infusion) the same. Dose–effect curves were determined when both infusions were delivered immediately and when delivery of the fixed dose was delayed (15–180 s). When both doses of remifentanil were delivered immediately, monkeys chose the large dose. Delaying delivery of the fixed dose reduced choice of that dose and increased choice of small immediately available doses. Extending previous studies, these results show that the effects of delay on choice between two doses of a &mgr;-opioid receptor agonist are consistent with hyperbolic discounting. Delaying delivery of a preferred reinforcer (e.g. large dose of drug) reduces its effectiveness and increases the effectiveness of small immediately available doses. This effect of delay, particularly on drug self-administration, might contribute to drug abuse.

Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys

Opioid abusers discount delayed reinforcers more rapidly than nonusers; however, it is unclear whether chronic drug administration or its discontinuation impacts discounting. This study examined the impact of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Responding on one lever delivered one food pellet immediately; responding on another lever delivered two food pellets either immediately or after a delay (30–120 s) that increased within the session. Monkeys (n=3) responded for the large reinforcer when both reinforcers were delivered immediately and more for the smaller, immediately available reinforcer as the delay to delivery of the large reinforcer increased. When administered acutely, morphine (0.032–5.6 mg/kg) increased trial omissions and had variable effects on choice, with small doses decreasing and large doses increasing choice of the large delayed reinforcer. Chronic morphine administration (0.1 mg/kg/day to 3.2 mg/kg twice daily) reduced choice of the large delayed reinforcer in two monkeys, while increasing choice in a third monkey. Despite the development of tolerance to some effects (i.e. rightward shifts in dose–effect curves for the number of trials omitted) and evidence of mild opioid dependence (e.g. decrease in the number of trials completed, as well as body weight), discontinuation of treatment did not appear to systematically impact discounting. Overall, these results suggest that repeated opioid administration causes persistent effects on choice under a delay discounting procedure; however, differences in the direction of effect among individuals suggest that factors other than, or in addition to, changes in discounting might play a role.

Antinociceptive effects of mixtures of mu opioid receptor agonists and cannabinoid receptor agonists in rats: Impact of drug and fixed-dose ratio

ABSTRACT Pain is a significant clinical problem, and there is a need for effective pharmacotherapies with fewer adverse effects than currently available drugs (e.g., mu opioid receptor agonists). Cannabinoid receptor agonists enhance the antinociceptive effects of mu opioid receptor agonists, but it remains unclear which drugs and in what proportion will yield the most effective and safest treatments. The antinociceptive effects of the mu opioid receptor agonists etorphine and morphine alone and in combination with the cannabinoid receptor agonists &Dgr;9‐THC and CP55940 were studied in male Sprague‐Dawley rats (n = 16) using a warm water tail withdrawal procedure. The ratio of opioid to cannabinoid (3:1, 1:1, and 1:3) varied for each mixture. Drugs administered alone or as pairwise mixtures of an opioid and a cannabinoid dose‐dependently increased tail withdrawal latency. Mixtures with morphine produced supra‐additive (CP55940) and additive (&Dgr;9‐THC) effects, whereas mixtures with etorphine and either cannabinoid were sub‐additive. The interactions were not different among ratios for a particular mixture. The nature of the interaction between opioids and cannabinoids with regard to antinociceptive effects varies with the particular drugs in the mixture, which can have implications for designing combination therapies for pain.