THE RATE-DECREASING EFFECTS OF FENTANYL DERIVATIVES IN PIGEONS BEFORE, DURING AND AFTER CHRONIC MORPHINE TREATMENT

Mirfentanil is a fentanyl derivative with nonopioid actions, including non-opioid antinociceptive effects in rhesus monkeys. The current stu dy examined the rate-altering effects of mirfentanil and several other compounds in pigeons to assess: 1) the opioid and non-opioid actions of acutely-administered fentanyl derivatives; and 2) the development o f cross-tolerance between each of these compounds and morphine. Seven pigeons responded under a fixed-ratio 20 (FR20) schedule of food deliv ery. In untreated pigeons, fentanyl, morphine, naltrexone, ketamine an d three fentanyl derivatives (mirfentanil, OHM3463 and OHM3295) decrea sed rates of key pecking in a dose-related manner. Naltrexone (0.1-1.0 mg/kg) attenuated the effects of OHM3463 and not mirfentanil or OHM32 95, suggesting non-opioid mediation of the rate-decreasing effects for the latter two fentanyl derivatives. Subjects were treated daily with morphine for 9 weeks, up to a dose of 100 mg/kg per day, during which time the dose-effect curves for morphine, fentanyl and OHM3463 shifte d rightward 6-, 10- and 2-fold, respectively, indicating the developme nt of tolerance to morphine and cross-tolerance to fentanyl and OHM346 3. Dose-effect curves for ketamine, OHM3295 and mirfentanil were not s hifted to the right during morphine treatment, and the dose-effect cur ve for naltrexone was shifted leftward 180-fold. To the extent that ra te-decreasing effects are predictive of antinociceptive effects, these data suggest that some fentanyl derivatives might be useful therapeut ics under conditions where tolerance develops to morphine-like opioids .