Enhancement of mu opioid antinociception by oral Delta(9)-tetrahydrocannabinol: Dose-response analysis and receptor identification

The antinociceptive effects of various mu opioids given p.o. alone and in c ombination with Delta-9-tetrahydrocannabinol (Delta(9)-THC) were evaluated using the tail-flick test. Morphine preceded by Delta(9)-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shif t from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED,, value when administered after Delta(9)-IHC (139.9 to 5.9 mg/kg). The dose-respons e curves for oxymorphone acid hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, I-alph a-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatmen t with Delta(9)-THC for heroin and meperidine indicated significant enhance ment (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta(9)-THC. Naloxone administration (1 m g/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta(9)-THC-induced enhancement of morphine and codei ne was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta(9)-THC. No effect was s een when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced b y an inactive dose of Delta(9)-THC p.o. The exact nature of this enhancemen t is unknown. We show evidence of involvement of mu and possibly delta opio id receptors as a portion of this signaling pathway that leads to a decreas e in pain perception.