Functional consequences of short-term exposure to opioids versus cannabinoids in nonhuman primates

Abstract

Opioids provide pain relief but are associated with several adverse effects. Researchers are exploring cannabis-based medicine as an alternative. However, little is known about the tendency for physical dependence on cannabinoids in comparison with that on opioids in primates. The aim of this study was to compare the potency of heroin and delta-9-tetrahydrocannabinol (THC) in eliciting analgesic effects and the development of physical dependence between opioids and cannabinoids in both male and female rhesus monkeys. Systemic administration of either heroin (0.03-0.18 mg/kg) or THC (0.3-1.8 mg/kg) in a dose-dependent manner produced antinociceptive effects against an acute thermal nociceptive stimulus. The μ-opioid receptor antagonist naltrexone (0.01 mg/kg) and the cannabinoid receptor antagonist SR141716A (0.3 mg/kg) produced the same degree of rightward shift in the dose-response curves for heroin- and THC-induced antinociception, respectively. Monkeys implanted with telemetry devices were subjected to short-term repeated administrations (two injections per day for 1-3 days) of either heroin (0.18 mg/kg), morphine (1.8 mg/kg), THC (1.8 mg/kg), or CP 55,940 (0.032 mg/kg). Administration of naltrexone (0.01 mg/kg) increased respiration, heart rate, and blood pressure in heroin- or morphine-treated monkeys. In contrast, administration of SR141716A (0.3 mg/kg) did not cause a significant change in these physiological parameters in THC- or CP 55,940-treated monkeys. Additionally, morphine, but not CP 55,940, enhanced the monkeys' hypersensitivity to the algogen capsaicin. Collectively, these results demonstrate that in nonhuman primates, both opioids and cannabinoids exert comparable antinociception; however, physical dependence on opioids, but not cannabinoids, at their antinociceptive doses, occurs following short-term exposures.

Keywords: Antinociception; CP 55,940; Heroin; Hypersensitivity; Morphine; Physical dependence; THC.

Figure 1.

Comparison of the antinociceptive effects of subcutaneously administered heroin and delta-9-tetrahydrocannabinol (THC) in monkeys. (A, B) Antinociception against acute noxious stimulus (50°C water). (C) Effect of opioid-receptor antagonist naltrexone (0.01 mg/kg) on heroin-induced antinociception. (D) Effect of cannabinoid-receptor antagonist SR141716A (0.3 mg/kg) on THC-induced antinociception. Each data point represents mean ± standard deviation (n = 4). Data were analyzed using two-way analysis of variance with repeated measures, followed by Bonferroni’s multiple comparisons test. *p < 0.05, significantly different from the vehicle-treated condition at 0.5–3 hr.

Figure 2.

Comparison of precipitated withdrawal signs in monkeys from short-term repeated administration of either heroin or delta-9-tetrahydrocannabinol (THC). Heroin (0.18 mg/kg) or THC (1.8 mg/kg) was administered twice per day for 1–3 days. The antagonists naltrexone (0.01 mg/kg) or SR141716A (0.3 mg/kg) were used to precipitate withdrawal signs on the next day after the last administration of agonists. Antagonist-precipitated withdrawal signs were measured in monkeys implanted with telemetry probes before and after antagonist treatment. (A, E) Respiration rate. (B, F) Minute volume. (C, G) Heart rate. (D, H) Mean arterial pressure. Data are shown as changes from the baselines (before antagonist treatment). Each data point represents mean ± standard deviation (n = 4) of each individual datum averaged from a 15-min time block. All drugs were delivered using an intramuscular route. Data were analyzed using two-way analysis of variance with repeated measures, followed by Bonferroni’s multiple comparisons test. *p < 0.05, significantly different from the vehicle-treated condition from 15–30 min to the corresponding time point.

Figure 3.

Comparison of precipitated withdrawal signs in monkeys from short-term repeated administration of either morphine or CP 55,940. Morphine (1.8 mg/kg) or CP 55,940 (0.032 mg/kg) was administered twice per day for 1–3 days. The antagonists naltrexone (0.01 mg/kg) or SR141716A (0.3 mg/kg) were used to precipitate withdrawal signs on the next day after the last administration of agonists. Antagonist-precipitated withdrawal signs were measured in monkeys implanted with telemetry probes before and after antagonist treatment. (A, E) Respiration rate. (B, F) Minute volume. (C, G) Heart rate. (D, H) Mean arterial pressure. Data are shown as changes from the baselines (before antagonist treatment). Each data point represents mean ± standard deviation (n = 4) of each individual datum averaged from a 15-min time block. All drugs were delivered using an intramuscular route. Data were analyzed using two-way analysis of variance with repeated measures, followed by Bonferroni’s multiple comparisons test. *p < 0.05, significantly different from the vehicle-treated condition from 15–30 min to the corresponding time point.

Figure 4.

Comparison of hypersensitivity to capsaicin-induced thermal allodynia from administration of morphine or CP 55,940. (A) Time course of topical capsaicin-induced thermal allodynia (46°C water). (B, C) Morphine (1.8 mg/kg) or CP 55,940 (0.032 mg/kg) was administered twice on day 1 before measuring tail-withdrawal latencies in 46°C water following topical capsaicin (0.4 mg/mL, 0.3 mL) application on day 2. Each data point represents mean ± standard deviation (n = 6). Data were analyzed using two-way analysis of variance with repeated measures, followed by Bonferroni’s multiple comparisons test. *p < 0.05, significantly different from the vehicle-treated condition from 15–60 min to the corresponding time point. #p < 0.05, significantly different from capsaicin 0.4 mg/mL at 15–60 min.