TOLERANCE AND CROSS-TOLERANCE TO THE RATE-SUPPRESSING EFFECTS OF OPIOIDS IN BUTORPHANOL TREATED RATS - INFLUENCE OF MAINTENANCE DOSE AND RELATIVE EFFICACY AT THE MU-RECEPTOR

The purpose of the present investigation was to examine the developmen t of tolerance to the rate-suppressing effects of mu and kappa opioids in rats administered either 3.0 (low) or 30 (high) mg/kg per day of b utorphanol, an opioid with low relative efficacy at the mu receptor. T he mu opioids butorphanol, buprenorphine, morphine, fentanyl and sufen tanil, and the kappa opioid U50,488 dose-dependently suppressed respon ding under all conditions examined. In rats administered the low maint enance dose of butorphanol, tolerance developed to the effects of buto rphanol, buprenorphine and morphine, but not to fentanyl and sufentani l. In rats administered the high maintenance dose, tolerance developed to all of the mu opioids examined. In both treatment groups, the degr ee to which tolerance developed was greater for butorphanol and bupren orphine than for morphine, fentanyl and sufentanil; and the degree to which tolerance developed to these mu opioids was greater in rats admi nistered the high maintenance dose of butorphanol. The tolerance that developed to morphine, fentanyl and sufentanil was not altered when te sted at both 23 and 47 h following the previous maintenance dose of bu torphanol, suggesting that these chang es were not due to any acute ph armacological interactions between butorphanol and the test compound ( i.e., antagonism). Tolerance was also conferred to the kappa opioid U5 0,488 in both groups of rats, and in rats administered the high mainte nance dose, this effect was obtained when tested 23 and 47 h following the previous maintenance dose of butorphanol. Physical dependence dev eloped in rats administered the high maintenance dose of butorphanol, as evidenced by the development of enhanced sensitivity to the rate-su ppressing effects of naloxone, and the finding that 30 mg/kg naloxone decreased body weight in a time-dependent manner. No physical dependen ce was apparent in rats administered the low maintenance dose of butor phanol. These data suggest that during chronic treatment with butorpha nol, (1) greater degrees of tolerance are conferred to drugs possessin g low efficacy at the mu opioid receptor, (2) tolerance is enhanced as the maintenance dose of the toleragen is increased, and (3) mu-opioid tolerance may be observed under conditions that do not produce mu-opi oid dependence.