Effect of alpha 2 adrenergic agents upon central etorphine antinociception in the cat

Systemic (s.c.) administration of alpha 2 agonists clonidine (25-100 micrograms/kg) or guanfacine (50-400 micrograms/kg) elicited antinociception as assessed by the cat tail-flick model and potentiated in a dose-dependent manner the antinociceptive effect of etorphine (2.5 micrograms) administered directly into the periaqueductal gray. Conversely, systemic yohimbine (1 mg/kg) attenuated the effects of central etorphine, and diminished potentiation of etorphine by the alpha 2 agonists. Prior microinjection of clonidine (5 micrograms) or guanfacine (5 micrograms) into the locus coeruleus (LC) reduced the intensity of central etorphine antinociception whereas central yohimbine (20 micrograms) pretreatment increased peak antinociceptive activity and prolonged the duration of etorphine. Thus, systemic alpha 2 agonists are inherently antinociceptive and potentiate central narcotic antinociception; however, the site of interaction between alpha 2 agonists and opiates does not appear to be the LC inasmuch as alpha 2 agonists attenuate the antinociceptive effect of etorphine when administered directly into the LC. A spinal site of action is suggested based upon known LC-spinal projections and our experimental observations.