Harmaline potentiates morphine-induced antinociception via affecting the ventral hippocampal GABA-A receptors in mice

Abstract

Morphine is one of the most effective medications for treatment of pain, but its side effects limit its use. Therefore, identification of new strategies that can enhance morphine-induced antinociception and/or reduce its side effects will help to develop therapeutic approaches for pain relief. Considering antinociceptive efficacy of harmaline and also highlighted the important role of GABA-A receptors in the pain perception, this research aimed to determine whether the ventral hippocampal (vHip) GABA-A receptors are involved in the possible harmaline-induced enhancement of morphine antinociception. To achieve this, vHip regions of adult male mice were bilaterally cannulated and pain sensitivity was measured in a tail-flick apparatus. Intraperitoneally administration of morphine (0, 2, 4 and 6 mg/kg) or harmaline (0, 1.25, 5 and 10 mg/kg) increased the percentage of maximal possible effect (%MPE) and induced antinociception. Interestingly, co-administration of sub-effective doses of harmaline (5 mg/kg) and morphine (2 mg/kg) induced antinociception. Intra-vHip microinjection of muscimol (0, 200 and 300 ng/mice), a GABA-A receptor agonist, enhanced the anti-nociceptive effects of harmaline (2.5 mg/kg)+morphine (2 mg/kg) combination. Microinjection of the same doses of muscimol into the vHip by itself did not alter tail-flick latency. Intra-vHip microinjection of bicuculline (100 ng/mouse), a GABA-A receptor antagonist, did not cause a significant change in MPE%. Bicuculline (60 and 100 ng/mouse, intra-vHip) was administered with the harmaline (5 mg/kg)+morphine (2 mg/kg), and inhibited the potentiating effect of harmaline on morphine response. These findings favor the notion that GABAergic mechanisms in the vHip facilitate harmaline-induced potentiation of morphine response in the tail-flick test in part through GABA-A receptors. These findings shall provide insights and strategies into the development of pain suppressing drugs.