Cannabinoid pretreatment blocks the development of tolerance to the analgesic effect of morphine injected into the periaqueductal gray
Wilson, A. & Morgan, M. M., Department of Psychology, Washington State University Vancouver
Cannabinoids and opioids are known to have analgesic effects. These drugs produce analgesia, in part, by acting on a brain structure called the periaqueductal gray (PAG). Unfortunately, the analgesia produced by opiates such as morphine is diminished with repeated administration because of the development of tolerance. The objective of this study was to determine whether tolerance develops to the analgesic effect of injecting the cannabinoid HU-210 into the PAG. Male Spraque-Dawley rats were implanted with a guide cannula aimed at the ventrolateral PAG. Following recovery, rats were injected twice a day for two days with saline, morphine, HU-210, or morphine and HU-210 combined. On Day 3 all rats received cumulative doses of morphine to determine whether tolerance had occurred. Nociception was assessed using the hot plate test. Both morphine and HU-210 caused an increase in hot plate latency compared to saline treated controls when injected into the PAG on Trial 1. Rats pretreated with morphine required higher doses of morphine to produce analgesia on Day 3 than saline-pretreated rats (i.e., the rats were tolerant). Surprisingly, rats pretreated with HU-210 required lower doses of morphine to produce analgesia on Day 3. Rats receiving morphine and HU-210 did not differ from saline-pretreated controls in their response to morphine. These data demonstrate that cannabinoid pretreatment enhances the analgesic effect of morphine and suggests that combined opiate and cannabinoid treatment be therapeutically advantageous by preventing the development of tolerance.