Evidence for crosstolerance to the analgesic effects between morphine and selective alpha 2-adrenoceptor agonists

Rats were injected subcutaneously (s.c.) with morphine (5 mg/kg) until tolerance developed to its antinociceptive action, or with 0.9% saline which was used as vehicle for morphine. Subsequently, both groups of animals were given an intrathecal (i.th.) dose of either noradrenaline (2 micrograms), clonidine (12.5 micrograms) or guanfacine (12.5 micrograms), that had been found previously to be reliably antinociceptive. In the saline-treated animals, these doses of noradrenaline, clonidine or guanfacine induced clear antinociceptive effects, but not in the morphine-group. It is therefore concluded that cross-tolerance to the antinociceptive effects of systemic morphine and the alpha-adrenoceptor agonists was obtained. The cross-tolerance between morphine on one hand, and noradrenaline, clonidine and guanfacine on the other, implies that a substantial opiate-adrenoceptor interaction exists in antinociceptive processes.