Disposition of morphine in chronically infused rats: relationship to antinociception and tolerance

Levels of morphine in brain and other biological materials were measured fluorometrically, and relationships were drawn to tail-flick activity and to tolerance development in rats treated chronically with the narcotic by i.p. infusion. Brain morphine concentration and tail-flick latency both increased with increasing dosage over the first 3 days of the 6-day infusion regimen. There was evidence of cellular tolerance within 24 to 48 hours after the beginning of infusion, with marked tolerance by day 6. Between days 3 and 6 a dispositional tolerance, evidenced by a dramatic fall in brain morphine concentration, also became apparent. After discontinuation of the infusion, the brain morphine dropped to extremely low levels by 24 hours, but significant tolerance to antinociceptive effects remained for 72 hours. Estimation of morphine in plasma, urine, peritoneal tissues and feces suggested several possible explanations for the dispositional tolerance observed. These include increased conjugation of morphine, increased fecal elimination and increased localization in muscle or peritoneal tissues with chronic infusion at relatively high doses. The present work thus examines the pharmacokinetics of morphine in the rat in a chronic treatment model that is currently being used in a number of laboratories for the rapid induction of drug tolerance and dependence.