Investigation of the effects of oxotremorine and amitriptyline on the development of morphine tolerance and dependence in mice

It has been reported that cholinergic and noradrenergic drugs have antinociceptive effects and reduce the development of tolerance to and dependence on morphine. Noradrenaline and serotonin reuptake inhibitor amitriptyline possesses similar effects also. Since amitrityline has marked anticholinergic activity, it can be suggested that these effects may change when amitriptyline is used with a muscarinic agonist. In the present study, mice were administered subcutaneously twice daily for 3 days with saline, 10 mg/kg amitriptyline, 0.1 mg/kg oxotremorine or a combination of amitriptyline and oxotremorine. On the first day, pain threshold was measured. Then the animals were implanted subcutaneously with placebo or morphine pellets and the time course of the antinociceptive effect after 4, 48 and 72 hours, the development of tolerance and withdrawal with naloxone were assessed. Amitriptyline demonstrated analgesic effect in the hot-plate and tail immersion tests and oxotremorine exerted in the tail immersion test. In the hot-plate test, oxotremorine abolished the analgesic effect of amitriptyline. The analgesic effect in the control-morphine group, while continued in the tail immersion test, disappeared in the hot plate test 48 hours later. The analgesic effect in the amitriptyline-morphine group lasted 48 hours in the hot plate test and 72 hours in the tail immersion test. The effect of morphine disappeared after 48 hours in the tail immersion test in the oxotremorine-morphine group. No change was observed in the amitriptyline-oxotremorine-morphine group in both tests. Response to morphine challenge was prevented by amitriptyline and was enhanced by oxotremorine. In naloxone induced withdrawal syndrome, weight loss was present in the amitriptyline-morphine group, but not in the control-morphine group. Other signs were less in the amitriptyline-oxotremorine-morphine group. Amitriptyline and oxotremorine produce analgesic effects possibly at the spinal and/or supraspinal level, amitriptyline reduces morphine tolerance while oxotremorine enhances it and amitriptyline enhances dependence while co-administration of amitriptyline and oxotremorine alleviates it. Evidence for the contribution of cholinergic and noradrenergic mechanisms to the development of analgesia, morphine tolerance and dependence, and their interaction should be supported by further studies. Key Words: morphine, tolerance, dependence, oxotremorine, amitriptyline, analgesia