Tolerance and cross tolerance to the accuracy- and rate-decreasing effects of mu opioids in rats responding under a fixed-consecutive-number schedule

Abstract

The purpose of the present investigation was to examine the development of tolerance to the effects of morphine and other mu opioids in rats responding under a fixed-consecutive-number (FCN) schedule of food presentation. To this end, five rats were trained under an FCN schedule and subsequently tested with a variety of mu opioids both before and during chronic exposure to a 0.4 mg/ml morphine drinking solution. Morphine, fentanyl, buprenorphine, butorphanol and nalbuphine produced dose-dependent decreases in both accuracy and response rate when tested prior to the chronic regimen. In most instances, doses of these drugs that decreased accuracy also decreased response rate. During chronic treatment, tolerance developed to the effects of morphine and cross-tolerance was conferred to the effects of fentanyl, buprenorphine and butorphanol. A greater degree of tolerance was conferred to the effects of butorphanol than to the other opioids examined, and the degree of tolerance conferred to butorphanol's rate-decreasing effects was greater than the degree of tolerance conferred to its accuracy-decreasing effects. Doses of naloxone that had no effect prior to morphine treatment produced large decreases in accuracy and response rate when tested during the chronic regimen. In contrast to the other opioids examined, the potency of nalbuphine was not altered by chronic morphine administration. These data emphasize the importance of both pharmacological and procedural variables in the development of tolerance and cross tolerance to the behavioral effects of opioids.