Potentiation of morphine-induced antinociception by harmaline: involvement of μ-opioid and ventral tegmental area NMDA receptors.

rationalMorphine is one of the most well-known and potent analgesic agents; however, it can also induce various side effects. Thus, finding drugs and mechanisms which can potentiate the analgesic effects of low doses of morphine will be a good strategy for pain management.

objectiveThe involvement of μ-opioid receptors and ventral tegmental area (VTA) glutamatergic system in harmaline and morphine combination on the nociceptive response were investigated. Also, we examined reward efficacy and tolerance expression following the drugs.

methodsAnimals were bilaterally cannulated in the VTA by stereotaxic instrument. A tail-flick (TF) apparatus and conditioned place preference (CPP) paradigm were used to measure nociceptive response and rewarding effects in male NMRI mice respectively.

resultsMorphine (2 mg/kg, i.p.) had no effect in TF test. Also, harmaline (1.25 and 5 mg/kg, i.p.) could not change pain threshold. Combination of a non-effective dose of harmaline (5 mg/kg) and morphine (2 mg/kg) produced antinociception and also prevented morphine tolerance but had no effect on the acquisition of CPP. Systemic administration of naloxone (0.5 and 1 mg/kg) and intra-VTA microinjection of NMDA (0.06 and 0.1 μg/mouse) before harmaline (5 mg/kg) plus morphine (2 mg/kg) prevented antinociception induced by the drugs. D-AP5 (0.5 and 1 μg/mouse, intra-VTA) potentiated the effect of low-dose harmaline (1.25 mg/kg) and morphine (2 mg/kg) and induced antinociception. Microinjection of the same doses of NMDA or D-AP5 into the VTA alone had no effect on pain threshold.

conclusionThe findings showed that harmaline potentiated the analgesic effect of morphine and reduced morphine tolerance. Glutamatergic and μ-opioidergic system interactions in the VTA seem to have a modulatory role in harmaline plus morphine-induced analgesia.