Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice

The antinociceptive effects of various cannabinoids, alone and in combination with opiates, were evaluated in antinociceptive tests in mice. The cannabinoids tested produce marked antinociceptive effects after i.t. administration to mice. The rank order of potency for the drugs using the tail-flick test was levonantradol greater than CP-55,940 = CP-56,667 greater than 11-hydroxy-delta 9-THC greater than delta 9-THC greater than delta 8-THC; dextronantradol was inactive at a dose of 25 micrograms/mouse. Respective ED50 values in the tail-flick test were 0.4, 12.3, 4.2, 15, 45 and 72 micrograms/mouse. Although pretreatment with morphine somewhat enhanced the effects of delta 9-THC, pretreatment of the mice with naloxone (1 mg/kg s.c. or 1 micrograms/mouse i.t.) failed to block the antinociceptive effects of the cannabinoids, indicating that the cannabinoid-induced antinociception does not occur due to direct interaction with the opiate receptor. Pretreatment of mice with 3.13 micrograms/mouse and 6.25 micrograms/mouse of delta 9-THC shifted the ED50 of morphine to 0.15 and 0.05 micrograms/mouse, respectively (a 4-and a 12-fold shift). The shifts in the dose-response curve of the morphine were parallel. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of the combination of 6.25 micrograms of delta 9-THC with morphine. The AD50 for naloxone blockade of the drug combination was 0.24 (0.06-0.94) mg/kg s.c. and the pA2 was 7.7 (6.7-8.9). The pA2 for naloxone blockade of the dimethylsulfoxide-morphine combination was 6.9 (5.7-8.1).(ABSTRACT TRUNCATED AT 250 WORDS)