Improving the analgesic effectiveness of opioids while also reducing the adverse effects is a major goal of pain research.
One approach to this problem has been to combine drugs such as cannabinoids with opioids to determine if this might reduce the dose of opioid required to produce analgesia.
In this experiment, male nonhuman primates (rhesus macaques) were administered a range of doses of THC in combination with cumulative doses of heroin to determine if the combinations produced greater analgesia than that observed with heroin alone.
Briefly, the animals were secured in standard primate ch airs, tails were shaved, and dipped in a mixed order in three different water temperatures (40 °, 50 °, and 55 °C) until the animal rapidly withdrew his tail, or 20 seconds elapsed.
Therefore, latency (sec) to remove the tail was converted to % maximum effect (%MPE). Each set of tail dips was separated by a 15-min period that also served as an injection interval for the cumulative doses of drug. The initial tail dips of a session served as the baseline, whereas the initial injections were either vehicle (control) or THC (0.056–0.18mg/kg, i.m.). Sessions usually occurred once per week, and occasionally, twice per week.
Prior to testing THC and heroin in combination, buprenorphine (n=7), morphine (n=4), and heroin (n=7) were administered alone (0.032–3.2 mg/kg, i.m.) for comparison purposes.
These same opioid agonists were also administered after the THC-heroin combinations.
At the doses of each drug tested, the rank order of analgesic effectiveness was heroin>buprenorphine>morphine, with maximum %MPE differing between the two high temperatures. For 50°C, the %MPE were 60%, 29%, and 27%, respectively. For 55°C, %MPE were 42%, 16%, and 7%, respectively.
When THC was administered prior to heroin, there was a similar one-half log leftward shift in the heroin dose-effect curve produced by all three doses of THC.
Unexpectedly, the leftward shift in the heroin dose-effect curve was still evident in the absence of THC when heroin alone was re-determined after a drug-free period of approximately 1 week.
These effects were mediated by mu opioid receptors since naltrexone (0.1mg/kg) reversed the analgesic effects of heroin at both water temperatures.
A leftward shift in the morphine dose-effect curve was also evident 2–3 weeks after the THC-heroin combinations.
Unlike heroin and morphine, the dose-effect curve for buprenorphine was not shifted relative to the initial curve; however, it was tested almost 2 months after the THC-heroin combinations.
In conclusion, acute doses of THC administered as a pretreatment potentiated the analgesic effects of heroin acutely, and for an extended period after the administration of the combination.