GABA_B receptors modulate morphine antinociception: Pharmacological and genetic approaches

Previous studies in our laboratory showed an interaction between the GABAergic and opioid systems involved in the analgesic effect of baclofen (BAC). Furthermore, it is known that sex differences exist regarding various pharmacological responses of morphine (MOR) and they are related to an increased sensitivity to MOR effects in males. The aims of the present study were to evaluate the possible involvement of the GABA_B receptors in the antinociceptive responses induced by MOR (1, 3 and 9 mg/kg, s.c.) administration using both pharmacological (BAC 2 mg/kg, i.p.; and 2-OH-saclofen, SAC 0.3 mg/kg, intra cisterna magna) and genetic approaches (GABA_B1 knockout mice; GABA_B1 KO) in mice of both sexes. In addition, we explored the alterations in c-Fos expression of different brain areas involved in the antinociceptive effect of MOR using both approaches. The pharmacological approach showed a higher dose-dependent antinociceptive effect of MOR in male mice compared to female mice. BAC and SAC pretreatment potentiated and attenuated the antinociceptive effect of MOR, respectively, in both sexes. The genetic approach revealed a dose-dependent antinociceptive effect of MOR in the wild type mice, but not in the GABA_B1 KO mice and no sex differences were observed. Additionally, BAC and SAC pretreatment and the lack of GABA_B1 subunit of the GABA_B receptor prevented the changes observed in c-Fos expression in the cingulate cortex and nucleus accumbens of male mice. Our results suggest that the GABA_B receptors are involved in the MOR antinociceptive effect of both male and female mice.