Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence.

Cannabidiol (CBD) is a constituent of the cannabis plant with a diverse array of pharmacological activities as well as potential therapeutic uses. An oral formulation of CBD (Epidiolex in the US; Epidyolex in Europe) is approved for treating seizures associated with rare and severe forms of epilepsy. These studies, which supported the approval of the medication, investigated abuse-related effects of CBD in rats and nonhuman primates (NHPs) using drug self-administration, drug discrimination, and physical dependence procedures and characterized its pharmacokinetics. In NHPs (n = 5) that self-administered midazolam (0.01 or 0.032 mg/kg/infusion), CBD (0.1-3.2 mg/kg/infusion) failed to maintain responding above vehicle levels. CBD maintained very modest levels of self-administration in rats (n = 7-8) that self-administered heroin (0.015 mg/kg/infusion) and did not increase drug-lever responding, up to a dose of 150 mg/kg (by mouth), in rats (n = 6) trained to discriminate 0.5 mg/kg (i.p.) midazolam. In juvenile (5-6 weeks old) and adult (10-11 weeks old) male and female rats, discontinuation of chronic treatment (twice daily for 20 days) with an oral formulation of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs of withdrawal. Pharmacokinetic studies confirmed that the dosing regimens used in these studies resulted in therapeutically relevant plasma levels. Taken together, the lack of reliable self-administration, the failure to increase drug-lever responding in rats trained to discriminate midazolam, and the absence of withdrawal signs upon discontinuation of chronic treatment indicate that CBD has very low abuse potential and is unlikely to produce physical dependence. SIGNIFICANCE STATEMENT: Legalization of cannabis across the United States and elsewhere has led to intense investigation into the safety and therapeutic potential of cannabis and its constituent materials, including cannabidiol (CBD). Results of these preclinical abuse potential studies on CBD indicate no rewarding properties, physical dependence potential, or similarity to a benzodiazepine. Together with data from in vitro pharmacology and human abuse potential studies, the abuse potential of Epidiolex in humans is likely to be negligible.

Combined Treatment with Morphine and Δ9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal.

Opioid receptor agonists are effective for treating pain; however, tolerance and dependence can develop with repeated use. Combining opioids with cannabinoids can enhance their analgesic potency, although it is less clear whether combined treatment alters opioid tolerance and dependence. In this study, four monkeys received 3.2 mg/kg morphine alone or in combination with 1 mg/kg Δ(9)-tetrahydrocannabinol (THC) twice daily; the antinociceptive effects (warm water tail withdrawal) of morphine, the cannabinoid receptor agonists WIN 55,212 [(R)-(1)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate] and CP 55,940 (2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-5-(2-methyloctan-2-yl)phenol), and the κ opioid receptor agonist U-50,488 (trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate) were examined before, during, and after treatment. To determine whether concurrent THC treatment altered morphine dependence, behavioral signs indicative of withdrawal were monitored when treatment was discontinued. Before treatment, each drug increased tail withdrawal latency to 20 seconds (maximum possible effect). During treatment, latencies did not reach 20 seconds for morphine or the cannabinoids up to doses 3- to 10-fold larger than those that were fully effective before treatment. Rightward and downward shifts in antinociceptive dose-effect curves were greater for monkeys receiving the morphine/THC combination than monkeys receiving morphine alone. When treatment was discontinued, heart rate and directly observable withdrawal signs increased, although they were generally similar in monkeys that received morphine alone or with THC. These results demonstrated that antinociceptive tolerance was greater during treatment with the combination, and although treatment conditions were sufficient to result in the development of dependence on morphine, withdrawal was not markedly altered by concurrent treatment with THC. Thus, THC can enhance some (antinociception, tolerance) but not all (dependence) effects of morphine.

Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys.

RATIONALE: Upon discontinuation of chronic opioid treatment, withdrawal typically peaks in 1-3 days and decreases markedly within 1 week; however, persistent physiological changes have been reported long after other signs have waned. OBJECTIVE: The goal of this study was to compare the discriminative stimulus, directly observable signs, and physiological effects of withdrawal in morphine-treated monkeys. MATERIALS AND METHODS: Monkeys received 5.6 mg/kg/12 h morphine and discriminated 0.0178 mg/kg naltrexone while responding under a fixed-ratio 5 schedule of stimulus-shock termination. Drug discrimination, behavioral observation, and telemetry were used to monitor the emergence of withdrawal, as well as any persistent changes, following discontinuation of morphine treatment. RESULTS: Naltrexone dose (0.001-0.032 mg/kg, s.c.) was positively related with indices of withdrawal. In the discrimination study, monkeys responded on the naltrexone lever 1-5 days following discontinuation of treatment; thereafter, they responded exclusively on the saline lever. After discontinuation of morphine, the frequency of observable signs peaked within 2-3 days and most were not significantly increased after 5 days. In contrast, increased heart rate and body temperature persisted for 14 days, returning to values obtained prior to discontinuation by 21 days. CONCLUSIONS: To the extent that discriminative stimulus effects of withdrawal in nonhumans are predictive of subjective reports of withdrawal in humans, these data indicate that effective treatments for opioid dependence must address not only the short-term subjective components of withdrawal but also, and perhaps more importantly, lingering behavioral and physiological effects that might contribute to relapse long after chronic drug use is discontinued.

Effects of pregnanolone in rats discriminating cocaine.

The discriminative stimulus effects of cocaine are typically attributed to its ability to increase dopaminergic transmission, although drugs that have different mechanisms of action can substitute for cocaine and modulation of the GABA(A) receptor system has been reported to alter its discriminative effects. Therefore, a discrimination procedure was used to extend the characterization of cocaine's discriminative effects and to examine the interaction between cocaine and pregnanolone, a drug that can modulate the GABA(A) receptor complex. Rats (n=15) were trained to discriminate saline from 5.6 or 10 mg/kg of cocaine under a fixed-ratio (FR) 20 schedule of food presentation. The dopamine releaser d-amphetamine and two monoamine uptake inhibitors bupropion and desipramine substituted for cocaine. In contrast, the positive GABA(A) modulators pregnanolone and lorazepam and the opioid agonist morphine did not substitute for cocaine. When administered prior to cocaine, the D(2) receptor antagonist haloperidol and pregnanolone, but not lorazepam, produced a small rightward shift of the cocaine dose-effect curve. The results of the present studies suggest that the discriminative stimulus effects of cocaine are not solely mediated by increases in dopaminergic transmission and that positive modulation of GABA(A) receptors by pregnanolone can alter these effects, albeit at doses that also decrease overall response rate.

Interaction of cocaine with positive GABAA modulators on the repeated acquisition and performance of response sequences in rats.

RATIONALE: Although positive GABA(A) modulators can attenuate several cocaine-induced behavioral effects, there is a paucity of data on their interaction with cocaine on transition behavior or learning. OBJECTIVES: The current study examined the effects of cocaine (3.2-32 mg/kg), pregnanolone (3.2-24 mg/kg), and lorazepam (0.1-10 mg/kg) alone and in combination in rats responding under a multiple schedule of repeated acquisition and performance. METHODS: In the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component, they responded on the same three-response sequence each session. RESULTS: All three drugs produced dose-dependent rate-decreasing and error-increasing effects. Cocaine was the least effective in decreasing rates and the most effective in increasing the percentage of errors. In combination with pregnanolone (3.2 or 10 mg/kg), the rate-decreasing effects of cocaine were relatively unchanged in both components, but 3.2 mg/kg of pregnanolone enhanced its error-increasing effects and the 10-mg/kg dose produced a significant dose-dependent interaction on errors. The combination of cocaine with lorazepam (0.32 mg/kg, 70-min pretreatment) produced significantly greater rate-decreasing and error-increasing effects than cocaine alone. A 15-min pretreatment with the same dose of lorazepam enhanced the error-increasing effects of small doses and attenuated the effects of larger doses of cocaine. Combinations of pregnanolone and lorazepam produced greater rate-decreasing and error-increasing effects in both components than either drug alone. CONCLUSIONS: The present data show that cocaine is more disruptive to learning in rats than pregnanolone or lorazepam, and that the disruptive effects of cocaine can be enhanced by CNS depressants.

Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys.

RATIONALE: Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if adverse effects are not similarly changed. OBJECTIVE: Cannabinoids have been shown to enhance the antinociceptive potency of opioids without increasing other effects; this study examined whether the effectiveness of cannabinoids is altered in morphine-dependent monkeys. METHODS: Four monkeys received up to 10 mg/kg morphine twice daily. Changes in the antinociceptive effects of opioid receptor agonists (morphine, U50,488) and cannabinoid receptor agonists (WIN 55,212, CP 55,940, and Δ(9)-tetrahydrocannabinol [THC]) were determined by measuring the latency for monkeys to remove their tails from 40, 50, 54, and 58 °C water. RESULTS: Before treatment, all drugs increased tail withdrawal latency from warm (54 °C) water. Chronic morphine treatment decreased the potency of each drug; the magnitude of rightward shift in dose-effect curves was greatest for morphine, WIN 55,212 and CP 55,940 with at least sixfold shifts for each drug during treatment. Discontinuation of morphine treatment resulted in signs that are indicative of withdrawal, including increased heart rate, decreased daytime activity, and tongue movement. CONCLUSION: Tolerance developed to the antinociceptive effects of morphine and cross-tolerance developed to cannabinoids under conditions that produced modest physical dependence. Compared with the doses examined in this study, much smaller doses of opioids have antinociceptive effects when given with cannabinoids; it is possible that tolerance will not develop to chronic treatment with opioid/cannabinoid mixtures.

Repeated administration of flumazenil does not alter its potency in modifying schedule-controlled behavior in chlordiazepoxide-treated rhesus monkeys.

Previous reports have suggested that the effects of the benzodiazepine antagonist flumazenil diminish over repeated exposure in subjects treated chronically with a benzodiazepine agonist. The current study examined whether the frequency of exposure to flumazenil altered its potency in decreasing rates of responding in monkeys treated with chlordiazepoxide (CDP). Three monkeys responded under a multiple fixed ratio (FR10:FR10) schedule of food presentation and stimulus-shock termination (SST). In untreated monkeys, flumazenil (0.1-3.2 mg/kg) had no effect in either component. After 2 weeks of treatment with 32.0 mg/kg per day of CDP, flumazenil decreased response rates in the food component, with a dose of 3.2 mg/kg decreasing rates to 10% of control; rates in the SST component were not altered by flumazenil. When flumazenil dose-effect curves were redetermined at 28-, 14-, 7-, 4-, 2- or 1-day intervals, there was no further change in the potency of flumazenil in decreasing food-maintained responding. When CDP treatment was terminated, the potency of flumazenil recovered to pre-CDP values within 23 days. These results suggest that dependence develops to CDP, since changes in the potency of flumazenil co-varied with CDP treatment. Moreover, it does not appear as though results from previous reports, that showed a diminished response to frequently-administered flumazenil, can be generalized to all conditions.

Discriminative stimulus effects of flumazenil in untreated and in diazepam-treated rhesus monkeys.

RATIONALE: Long-term use of benzodiazepine agonists can have adverse effects (e.g., development of dependence), thereby limiting their clinical usefulness. OBJECTIVES: The goal of the current study was to examine the discriminative stimulus effects of flumazenil in untreated and diazepam-treated monkeys to determine whether this type of procedure could be used to examine benzodiazepine dependence. METHODS: Flumazenil (0.32 mg/kg s.c.) was established as a discriminative stimulus in eight monkeys receiving 5.6 mg/kg/day of diazepam (p.o.); four responded under a fixed ratio (FR)5 schedule of stimulus-shock termination (SST) and four responded under a FR5 schedule of food presentation. For comparison, 1.0 mg/kg flumazenil (s.c.) was established as a discriminative stimulus in four untreated monkeys responding under a FR5 schedule of SST. RESULTS: Flumazenil dose-dependently increased responding on the flumazenil-appropriate lever in all monkeys. In diazepam-treated monkeys, Ro 15-4513, ethyl beta-carboline-3-carboxylate and bretazenil substituted for flumazenil with pentylenetetrazole substituting in some monkeys; other drugs failed to substitute for flumazenil. Acute administration of 10.0 mg/kg diazepam (s.c.) shifted the flumazenil dose-effect curve threefold to the right of the control dose-effect curve. Temporary suspension of diazepam treatment produced a time-related increase in flumazenil-lever responding that was reversed by diazepam. In untreated monkeys, midazolam substituted for flumazenil, with other drugs, including those with primary mechanisms of action at non-gamma-aminobutyric acid(A) receptors, substituting in some monkeys. Ro 15-4513 did not substitute in any untreated monkey. CONCLUSIONS: The flumazenil discriminative stimulus appears to be pharmacologically selective in treated monkeys with only negative and low efficacy positive modulators substituting for flumazenil; in contrast, a variety of drugs substitute for flumazenil in untreated monkeys. This apparent difference in selectivity suggests that diazepam treatment modifies the flumazenil discriminative stimulus perhaps due to the development of dependence.

Studies on benzodiazepines and opioids administered alone and in combination in rhesus monkeys: ventilation and drug discrimination.

Benzodiazepines and opioids are co-administered recreationally as well as clinically; in the current study, the ventilatory-depressant and discriminative stimulus effects of several benzodiazepines and opioids were examined alone and in combination in order to evaluate any interaction between agonists from these pharmacological classes. The benzodiazepines alprazolam, diazepam, flunitrazepam, lorazepam, midazolam and triazolam and the opioids morphine and fentanyl decreased ventilation (V(E)) in monkeys breathing either air or 5% CO2 in air, although decreases in ventilation produced by opioids were greater in magnitude than decreases produced by benzodiazepines. Flumazenil antagonized the ventilatory-depressant effects of flunitrazepam and triazolam and not those of fentanyl; naltrexone antagonized the ventilatory-depressant effects of fentanyl and not those of flunitrazepam or triazolam. Interactions between the ventilatory-depressant effects of agonists from the two classes were less than additive. In monkeys receiving 3.2 mg/kg per day of morphine and discriminating 0.01 mg/kg naltrexone, neither flunitrazepam nor triazolam substituted for naltrexone; in morphine-deprived monkeys, morphine, and not flunitrazepam or triazolam, reversed naltrexone-lever responding. Moreover, benzodiazepines did not modify the discriminative stimulus effects of naltrexone in morphine-treated monkeys or of morphine in morphine-deprived monkeys. In contrast to studies showing synergism between benzodiazepines and opioids, the current study suggests that, under some conditions, combinations of these drugs can be administered without enhancing the ventilatory-depressant effects of either class of drugs or the discriminative stimulus effects of opioids.

The rate-decreasing effects of fentanyl derivatives in pigeons before, during and after chronic morphine treatment.

Mirfentanil is a fentanyl derivative with non-opioid actions, including non-opioid antinociceptive effects in rhesus monkeys. The current study examined the rate-altering effects of mirfentanil and several other compounds in pigeons to assess: 1) the opioid and non-opioid actions of acutely-administered fentanyl derivatives; and 2) the development of cross-tolerance between each of these compounds and morphine. Seven pigeons responded under a fixed-ratio 20 (FR20) schedule of food delivery. In untreated pigeons, fentanyl, morphine, naltrexone, ketamine and three fentanyl derivatives (mirfentanil, OHM3463 and OHM3295) decreased rates of key pecking in a dose-related manner. Naltrexone (0.1-1.0 mg/kg) attenuated the effects of OHM3463 and not mirfentanil or OHM3295, suggesting non-opioid mediation of the rate-decreasing effects for the latter two fentanyl derivatives. Subjects were treated daily with morphine for 9 weeks, up to a dose of 100 mg/kg per day, during which time the dose-effect curves for morphine, fentanyl and OHM3463 shifted rightward 6-, 10- and 2-fold, respectively, indicating the development of tolerance to morphine and cross-tolerance to fentanyl and OHM3463. Dose-effect curves for ketamine, OHM3295 and mirfentanil were not shifted to the right during morphine treatment, and the dose-effect curve for naltrexone was shifted leftward 180-fold. To the extent that rate-decreasing effects are predictive of antinociceptive effects, these data suggest that some fentanyl derivatives might be useful therapeutics under conditions where tolerance develops to morphine-like opioids.

Evaluation of the reinforcing and discriminative stimulus effects of gamma-hydroxybutyrate in rhesus monkeys.

Gamma-hydroxybutyrate (GHB) is a metabolite of GABA that is present in the CNS and fulfils at least some of the criteria for a neurotransmitter. Its effects are generally similar to those of CNS depressants and include ataxia, sleep and anesthesia. It has also been suggested that GHB is a drug of abuse. The present experiment was designed to evaluate GHB in procedures predictive of abuse and dependence potential in rhesus monkeys. Three monkeys were surgically prepared with indwelling silicone venous catheters and allowed to self-administer methohexital or saline in twice-daily experimental sessions. Other groups of monkeys were trained in drug discrimination paradigms to discriminate D-amphetamine (AMPH; n = 4), pentobarbital (PB; n = 3) or triazolam (n = 3) from saline. Another group was maintained on diazepam daily and trained to discriminate flumazenil from saline (n = 2). GHB (0.01-10 mg/kg per injection) maintained self-administration marginally above saline levels at one dose (3.2 or 10 mg/kg) in two of the three monkeys tested. GHB (1.0-178 mg/kg, subcutaneously (s.c.) or intragastrically (i.g.)) did not reliably substitute as a discriminative stimulus for any of the training conditions. Taken together with previous results, the present experiment suggests that GHB has, at most, low potential for abuse.

Behavioral effects of flunitrazepam: reinforcing and discriminative stimulus effects in rhesus monkeys and prevention of withdrawal signs in pentobarbital-dependent rats.

Flunitrazepam was evaluated in several procedures that have been used extensively to study the behavioral effects and abuse potential of positive GABA(A) modulators. One group of monkeys (n=3) responded to receive injections of methohexital or saline (i.v.) while other groups (n=2-4/group) discriminated vehicle from either pentobarbital or triazolam. Other monkeys (n=2) received diazepam daily and discriminated flumazenil from vehicle. Finally, the ability of flunitrazepam to prevent the emergence of withdrawal signs in pentobarbital-treated rats was evaluated. Flunitrazepam maintained i.v. self-administration that was, on average, less than that maintained by methohexital and greater than that maintained by saline. In drug discrimination studies, flunitrazepam substituted for pentobarbital and for triazolam and failed to substitute for flumazenil. In rats (n=3-6/group), signs of withdrawal were not evident when flunitrazepam treatment replaced pentobarbital treatment; withdrawal signs emerged when either pentobarbital or flunitrazepam treatment was terminated. Taken together with data from previous studies, these data suggest that the abuse liability of flunitrazepam is comparable to that of other benzodiazepines.

Changes in sensitivity to the rate-decreasing effects of opioids in pigeons treated acutely or chronically with nalbuphine.

This study examined whether tolerance or dependence develops to the effects of the low-efficacy µ opioid agonist nalbuphine on schedule-controlled responding. In untreated pigeons responding under a fixed ratio (FR)-20 schedule of food presentation, nalbuphine, naltrexone, morphine, fentanyl, etonitazene and enadoline decreased response rates. Naltrexone (0.1-10.0mg/kg) did not antagonize the rate-decreasing effects of nalbuphine. In a separate group of pigeons, chronic nalbuphine treatment (1.0-56.0mg/kg/day) did not alter the sensitivity of pigeons to the rate-decreasing effects of nalbuphine or naltrexone. In pigeons treated with 56.0mg/kg/day of nalbuphine, dose-effect curves for µ and kappa agonists were shifted 3- to 10-fold to the right of dose-effect curves determined prior to chronic treatment. The rate-decreasing effects of nalbuphine did not appear to be mediated by opioid receptors, as evidenced by the inability of naltrexone to antagonize nalbuphine and the lack of tolerance development. Although chronic nalbuphine altered the sensitivity to the rate-decreasing effects of µ and kappa agonists, there was no change in sensitivity to naltrexone. To the extent that increased sensitivity to antagonists is indicative of dependence, these data suggest that opioid dependence does not develop to nalbuphine.

Discriminative stimulus effects of flumazenil in rhesus monkeys treated chronically with chlordiazepoxide.

Discriminative stimulus effects of the benzodiazepine antagonist flumazenil were studied in two rhesus monkeys receiving 3.2 mg/kg/12 h of chlordiazepoxide while discriminating between vehicle and 0.056 mg/kg of flumazenil. In a drug discrimination component responding was maintained under a FR 10 schedule of stimulus-shock termination; in a non-discrimination component responding was maintained under a FR 10 schedule of food presentation. Flumazenil and Ro 15-4513 occasioned >80% flumazenil-lever responding at doses larger than 0.032 and 0.056 mg/kg, respectively. Pentylenetetrazole, ethyl-beta-carboline-3-carboxylate (betaCCE), ketamine and spiradoline failed to substitute for flumazenil although >80% drug-lever responding was observed for two of the compounds in one monkey. Flumazenil, Ro 15-4513, pentylenetetrazole, betaCCE but not ketamine or spiradoline decreased rates of responding in the food component at doses that had little effect on rates in the stimulus-shock termination component. When chlordiazepoxide injections were discontinued and saline was administered before the session, monkeys did not respond on the flumazenil lever; when flumazenil was administered under the same conditions, monkeys responded on the flumazenil lever despite not having received chlordiazepoxide for nine days. Drug stimulus control was established with flumazenil in monkeys receiving chlordiazepoxide and substitution studies suggest that this effect of flumazenil might result from antagonist actions at benzodiazepine receptors: however, lack of withdrawal-related effects after termination of chlordiazepoxide treatment precludes validation of this procedure for studying benzodiazepine dependence.

Ventilatory effects of negative GABA(A) modulators in rhesus monkeys.

This study examined changes in ventilation produced by negative gamma-aminobutyric acid(A) (GABA(A)) modulators in rhesus monkeys. The effects of Ro 15-4513, beta-CCE and beta-CCM were examined in four rhesus monkeys breathing air or 5% CO2 in air. When monkeys breathed CO2, minute volume (VE) and frequency (f) increased, on average, to 158 and 140% of control (air), respectively. Ro 15-4513 did not modify ventilation in monkeys breathing either gas mixture; however, beta-CCE and beta-CCM increased VE and f in monkeys breathing air to between 123 and 141% of control and had no effect on ventilation of 5% CO2. Increased ventilation produced by the negative GABA(A) modulators appeared to be maximal, because ventilation was not further enhanced when the dose was increased three-fold. Each of the three negative GABA(A) modulators reversed the decreases in ventilation produced by diazepam, suggesting that these drugs are acting at benzodiazepine receptors; however, the increased ventilation produced by beta-CCE and beta-CCM might suggest that they have more negative efficacy than Ro 15-4513. These data extend previous findings by showing that some negative GABA(A) modulators (Ro 15-4513) do not alter ventilation and further indicate that changes in ventilation can be used to evaluate efficacy differences among GABA(A) modulators.

Effects of a novel fentanyl derivative on drug discrimination and learning in rhesus monkeys.

Three monkeys discriminated 1.78 mg/kg of mirfentanil while responding under a fixed-ratio 5 schedule of stimulus-shock termination. Two mirfentanil derivatives, OHM3295 and OHM10579, substituted for mirfentanil in all subjects. However, other drugs produced variable effects among monkeys; for example, mu and kappa opioid agonists and clonidine substituted for mirfentanil on some occasions in two monkeys. Cocaine, amphetamine, and ketamine did not substitute in any subject. Opioid antagonists did not attenuate the effects of mirfentanil. In monkeys responding under a repeated acquisition and performance procedure, errors increased only during the acquisition phase at doses of mirfentanil that decreased response rates. Thus, unlike fentanyl, the discriminative stimulus effects of mirfentanil do not appear to be mediated exclusively through opioid receptors. Finally, mirfentanil does not appear to disrupt complex behavioral processes.

Pharmacological profile of a deuterium-substituted mirfentanil derivative, OHM10579, in rhesus monkeys.

The discriminative-stimulus, respiratory, and antinociceptive effects of OHM10579, an isotopic isomer of mirfentanil, were characterized in rhesus monkeys. In monkeys discriminating nalbuphine, 0.32 mg/kg of OHM10579 partially substituted for nalbuphine. In monkeys treated daily with 3.2 mg/kg of morphine and discriminating 0.01 mg/kg of naltrexone, 0.32 mg/kg of OHM10579 substituted for naltrexone. In morphine-abstinent monkeys, morphine reversed naltrexone-lever responding, an effect attenuated by OHM10579. The shift to the right in the morphine dose-effect curve was greater 2 h after 0.32 mg/kg of OHM10579 compared to 0.32 mg/kg of mirfentanil, indicating that OHM10579 has a longer duration of action than mirfentanil. In a warm-water tail-withdrawal procedure, 10 and 17.8 mg/kg of OHM10579 had antinociceptive effects that were not antagonized by naltrexone. Morphine decreased breathing in air to 48%, whereas the maximal decrease with OHM10579 was to 75% of control. OHM10579 attenuated hyperventilation induced by 5% CO2 and partially antagonized the respiratory-depressant effects of morphine. OHM10579 can be classified as a low-efficacy mu-opioid agonist with some nonopioid actions. These results indicate that the pharmacology of the mirfentanil isotope OHM10579 is similar to that of mirfentanil, but that OHM10579 might have a longer duration of action.

Behavioral effects of 6-methylene naltrexone (nalmefene) in rhesus monkeys.

Nalmefene [17-N-cyclopropylmethyl-3,14-beta-dihydroxy-4,5-alpha-epoxy-6- methylenemorphinan hydrochloride (also NIH 10365)], a 6-methylene derivative of naltrexone, was compared to naltrexone for its behavioral effects in rhesus monkeys. Nalmefene had opioid antagonist actions under all conditions, having a potency similar to that of naltrexone. In morphine-treated monkeys, discriminating between 0.01 mg/kg of naltrexone and saline, nalmefene substituted completely for naltrexone at doses larger than 0.001 mg/kg. The onset of discriminative stimulus effects was similar for nalmefene and naltrexone. A dose of 0.032 mg/kg of either antagonist occasioned > or = 90% naltrexone-level responding beginning 6 to 8 min after s.c. administration; the effects of this dose of either antagonist persisted for more than 1 hr. Like the parent compound naltrexone, nalmefene also antagonized the discriminative stimulus effects of opioid agonists. Nalmefene prevented the discriminative stimulus effects of morphine in monkeys acutely deprived of morphine and antagonized the discriminative stimulus effects of nalbuphine in a separate group of monkeys discriminating between nalbuphine and saline. At the dose of naltrexone and nalmefene that produced an equivalent antagonism of morphine when the antagonist was administered 0.25 hr before morphine (0.01 mg/kg), the duration of antagonist action was < 4 hr and > 6 hr, respectively. Nalmefene also attenuated the antinociceptive effects of the mu agonist alfentanil and the kappa agonist CI-977 [5R-(5,7,8-beta)-N-methyl- N-[7-(1-pyrrolidinyl)1-oxaspiro[4,5]dec-8-yl]-4-benzofuranaceta mide], being 55 times more potent in attenuating the antinociceptive effects of alfentanil as compared to Cl-977.(ABSTRACT TRUNCATED AT 250 WORDS)

Discriminative stimulus effects of nalbuphine in rhesus monkeys.

Three rhesus monkeys discriminated between 0.178 mg/kg of nalbuphine and saline while responding under a fixed-ratio 5 schedule of stimulus-shock termination. Nalbuphine produced dose-related increases in drug-lever responding with > or = 90% of responses occurring on the drug lever at doses larger than 0.1 mg/kg. The duration of action of the discriminative stimulus effects of nalbuphine was less than 5.25 hr. Rank order potency of compounds that substituted for the nalbuphine discriminative stimulus (i.e., > or = 90% responding on the nalbuphine lever) in all three subjects was fentanyl > butorphanol > methadone > morphine. Compounds that did not substitute completely in all monkeys included the kappa agonists ethylketocyclazocine, enadoline, spiradoline and U-50,488 and the nonopioids cocaine, d-amphetamine, clonidine, ketamine and phencyclidine. Naltrexone antagonized the discriminative stimulus effects of nalbuphine, shifting the nalbuphine dose-effect curve in a manner that was consistent with mu receptor mediation. Results from the current study demonstrate that, in rhesus monkeys, the discriminative stimulus effects of nalbuphine are mediated by mu opioid receptors. Although there is evidence suggesting that nalbuphine has kappa agonist effects (e.g., subjective effects in humans), results from several studies, including the current study, strongly suggest that in rhesus monkeys nalbuphine does not exert agonist actions at kappa receptors. Moreover, these data indicate that differences in behavioral effects between nalbuphine and prototypic mu opioids (e.g., morphine) probably result from differences in activity (e.g., efficacy) at mu receptors rather than any kappa agonist actions of nalbuphine.

Changes in sensitivity to the rate-decreasing effects of opioids in pigeons treated acutely or chronically with l-alpha-acetylmethadol.

The purpose of this study was to examine the effects of acute and chronic treatment with l-alpha-acetylmethadol (LAAM), a long-acting mu opioid agonist that is used to treat opioid dependence. In pigeons responding under an FR20 schedule of food presentation, LAAM decreased responding in a dose- and time-dependent manner, with the largest decrease occurring 4 hr after the administration of 5.6 mg/kg. Acute (1.0-5.6 mg/kg) or chronic (1.0-5.6 mg/kg/day) treatment with LAAM decreased sensitivity to morphine and increased sensitivity to naltrexone, although for both drugs changes in sensitivity were 3- to 10-fold greater during chronic treatment. Chronic LAAM treatment (5.6 mg/kg/day) also decreased sensitivity to fentanyl and etonitazene by 3-fold and increased sensitivity to nalorphine and nalbuphine by 30- and 6-fold, respectively; sensitivity to enadoline and ketamine increased only 2- to 3-fold. When LAAM treatment was temporarily suspended for 1 day, response rates decreased to 33% of control; this disruption was reversed by acute administration of morphine or etonitazene. Increased sensitivity to naltrexone and disruptions in responding when LAAM treatment was temporarily suspended indicate that dependence developed to LAAM. Tolerance and cross-tolerance to agonists as well as increased sensitivity to antagonists can be similar during chronic treatment with morphine or LAAM; however, increased sensitivity to nalbuphine during LAAM treatment is not typically observed during morphine treatment, suggesting that dependence on LAAM might not be identical to dependence on morphine. Finally, changes in sensitivity to other drugs might predict altered sensitivities to opioids and nonopioids in humans receiving LAAM.