Development of tolerance to the analgesic effect of clonidine in rats. Cross-tolerance to morphine.

The influence of chronic treatment with clonidine on analgesia produced by clonidine and morphine was studied in rats. Electrical stimuli were applied to the tail, and analgesia was measured as increase in the threshold voltage that elicited vocalisation. Twenty-two hours after the last of 14 injections of increasing doses of clonidine over 7 days, the acute analgesic effects of both clonidine and morphine were reduced, i.e. tolerance had developed. Pretest vocalisation thresholds (voltage) were unchanged by long-term treatment with clonidine, or, respectively, saline. Contrarywise, acute administration of clonidine enhanced the effect of morphine. The tolerance developed after long-term treatment with clonidine might be associated with changes in brain noradrenaline mechanisms.