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

Abstract

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.

Fig. 1.

Antinociceptive effects of morphine (left panels) and U-50,488 (right panels) in four monkeys before, during, and after chronic treatment with morphine alone or in combination with THC. (Top) Dose-effect curves determined before chronic treatment (squares) and on the 55th day of twice-daily treatment with either 3.2 mg/kg morphine alone (circles) or 3.2 mg/kg morphine and 1 mg/kg THC (triangles). (Second from top) Dose-effect curves determined before chronic treatment (squares, same curve as in top panel), on the 55th day of twice-daily treatment with 3.2 mg/kg morphine and 1 mg/kg THC (triangles, same curve as in top panel), and after discontinuation of treatment with the morphine/THC combination (half-filled triangles). (Second from bottom) Dose-effect curves determined before chronic treatment (squares, same curve as in top panel), on the 55th day of twice-daily treatment with 3.2 mg/kg morphine alone (circles, same curve as in top panel), and after discontinuation of treatment (half-filled circles). (Bottom) Area under dose-effect curves determined before (squares), during (triangles, circles), and after treatment (half-filled symbols). For clarity, morphine dose-effect curves determined 1 and 2 weeks after termination of treatment are not plotted in the middle panels (see lower panel). *The AUC is statistically different from the AUC obtained before chronic treatment. Ordinates: top three rows, latency (seconds) to remove tails from 54°C water averaged across monkeys (±S.E.M.); bottom, AUC. Abscissae: top 3 rows, saline (S) or opioid dose in milligrams per kilogram of body weight; bottom panels, morphine treatment condition (weeks 1, 2, 3, and 9 indicate the number of weeks since discontinuation of treatment).

Fig. 2.

Antinociceptive effects of WIN 55,212 (left) and CP 55,940 (right) in four monkeys before, during, and after chronic treatment with morphine alone or in combination with THC. (Top) Dose-effect curves determined before chronic treatment (squares) and on the 55th day of twice-daily treatment with either 3.2 mg/kg morphine alone (circles) or 3.2 mg/kg morphine and 1 mg/kg THC (triangles). (Second from top) Dose-effect curves determined before chronic treatment (squares, same curve as in top panel), on the 55th day of twice-daily treatment with 3.2 mg/kg morphine and 1 mg/kg THC (triangles, same curve as in top panel), and after discontinuation of treatment (half-filled triangles). (Second from bottom) Dose-effect curves determined before chronic treatment (squares, same curve as in top panel), on the 55th day of twice-daily treatment with 3.2 mg/kg morphine alone (circles, same curve as in top panel), and after discontinuation of treatment (half-filled circles). (Bottom) Area under dose-effect curves determined before (squares), during (triangles, circles), and after treatment (half-filled symbols). For clarity, cannabinoid dose-effect curves determined 4 and 6 weeks after termination of treatment are not plotted in the middle panels (see lower panel). *The AUC is statistically different from the AUC obtained before chronic treatment. Ordinates: top three rows, latency (seconds) to remove tails from 54°C water averaged across monkeys (±S.E.M.); bottom, AUC. Abscissae: top three rows, saline (S) or cannabinoid dose in milligrams per kilogram of body weight; bottom panels, morphine treatment condition (weeks 4, 6, 8, and 10 indicate the number of weeks since discontinuation of treatment).

Fig. 3.

Heart rate (top), body temperature (middle), and activity (bottom) in untreated monkeys (points above “before”), during treatment with 3.2 mg/kg morphine alone or in combination with 1 mg/kg THC (points above “during”), and after discontinuation of treatment. Data obtained during the light cycle (i.e., 1000–2000 hours) are shown in the left panels, and data obtained during the dark cycle (i.e., 2000–0600 hours) are shown in the right panels. *The point is significantly different from the point obtained before chronic treatment; #The point obtained during or after treatment with the combination is significantly different from the point obtained during or after treatment with morphine alone. Ordinates: upper panel, heart rate (beats per minute); middle panel, body temperature (°C); bottom panel, activity (counts per minute). Abscissa: days since discontinuation of treatment.

Fig. 4.

Total withdrawal signs (top) and unusual tongue movement (bottom) in untreated monkeys (points above “before”), during treatment with 3.2 mg/kg morphine alone or in combination with 1 mg/kg THC (points above “during”), and after discontinuation of treatment. Total withdrawal signs are a composite score of withdrawal determined by adding the frequency of the individual signs across each 8-minute observation period. Unusual tongue movement was the only sign that was significantly different during withdrawal, and therefore, it is the only sign plotted. *The point is significantly different from the point obtained before chronic treatment; #The point obtained after treatment with the combination is significantly different from the point obtained after treatment with morphine alone. Ordinates: frequency. Abscissa: days since discontinuation of treatment.