Abstract
The discriminative stimulus effects of several μ-opioid agonists were examined under conditions of opioid sensitization or tolerance, i.e., before and after 1-week SC infusions of naloxone or μ-opioid agonists. Rats were trained to discriminate 3.0 mg/kg morphine from saline using a two-lever, discrete trial, shock-avoidance/escape procedure. The rats generalized completely to morphine, fentanyl, meperidine, buprenorphine, and etorphine, and partially to pentazocine. A 7-day infusion of naloxone (0.3 mg/kg per h) potentiated the discriminative stimulus effects of all of these drugs. The magnitude of the increased potency varied indirectly with the efficacy of the μ-opioid agonists; potency ratios (pre-infusion ED50/post-infusion ED50) ranged from 1.58 (etorphine) to 3.58 (pentazocine). Stimulus generalization to morphine, fentanyl, and meperidine also was examined following infusions of equieffective doses of each of these three drugs. Differences among drugs were generally small, and failed to reach statistical significance. Nonetheless, the induction of μ-opioid tolerance did seem to vary with the efficacy of the three μ-opioid agonists. Thus, meperidine (6.25 mg/kg per h), which has the lowest efficacy of the drugs infused, produced the greatest shift to the right of the stimulus-generalization curves of these three drugs; the post-meperidine PR ranged between 0.40 and 0.61. Fentanyl (0.1 mg/kg per h), a drug with a higher efficacy at μ-opioid receptors, did not produce tolerance to the discriminative stimulus effects of morphine, fentanyl, or meperidine; potency ratios ranged from 0.50 to 0.75. Potency ratios for buprenorphine, etorphine, fentanyl, meperidine, and morphine after 7-day morphine infusions (0.75 mg/kg per h) ranged from 0.38 (buprenorphine) to 0.80 (etorphine). Morphine induced significant tolerance only to the discriminative stimulus effects of fentanyl. Our results suggest that different cellular mechanisms underlie the development of tolerance and sensitization to the discriminative stimulus effects of μ-opioid agonists.
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References
Adams JU, Paronis CA, Holtzman SG (1990) Assessment of relative intrinsic activity of mu-opioid analgesics in vivo using β-funaltrexamine. J Pharmacol Exp Ther 255:1027–1032
Ahtee L, Attila LMJ, Carlson KR (1990) Augmentation of morphine-induced changes in brain monoamine metabolism after chronic naltrexone treatment. J Pharmacol Exp Ther 255:803–808
Ayesta FJ, Ableitner A, Emmett-Oglesby MW, Herz A, Shippenberg TS (1992) Paradoxical effect of chronic fentanyl treatment on naltrexone-induced supersensitivity and upregulation. J Pharmacol Exp Ther 260:168–174
Bardo, MT, Niesewander, JL (1987) Chronic naltrexone supersensitizes the reinforcing and locomotor-activating effects of morphine. Pharmacol Biochem Behav 28:267–273
Bardo MT, Bhatnagar RK, Gebhart GF (1983) Chronic naltrexone increases opiate binding in brain and produces supersensitivity to morphine in the locus coeruleus of the rat. Brain Res 289:223–234
Colpaert FC, Kuyps JJMD, Niemegeers CJE, Janssen PAJ (1976) Discriminative stimulus properties of fentanyl and morphine: tolerance and dependence. Pharmacol Biochem Behav 5:401–408
Colpaert FC, Niemegeers CJE, Janssen PAJ, Van Ree JM (1978) Narcotic cueing properties of intraventricularly administered sufentanil, fentanyl, morphine, and met-enkephalin. Eur J Pharmacol 47:115–119
Craft RM, Picker MJ, Dykstra LA (1989) Differential cross-tolerance to opioid agonists in morphine-tolerant pigeons responding under a schedule of food presentation. J Pharmacol Exp Ther 249:386–393
Dahlström BE, Paalzow LK, Lindberg C, Bogentoft C (1979) Pharmacokinetics and analgesic effect of pethidine (meperidine) and its metabolites in the rat. Drug Metab Disp 7:108–112
Emmett-Oglesby MW, Shippenberg TS, Herz A (1988) Tolerance and cross-tolerance to the discriminative stimulus properties of fentanyl and morphine. J Pharmacol Exp Ther 245:17–23
Emmett-Oglesby MW, Shippenberg TS, Herz A (1989) Fentanyl and morphine discrimination in rats continuously infused with fentanyl. Behav Pharmacol 1:3–11
Hug CC, Murphy MR (1981) Tissue redistribution of fentanyl and termination of its effects in rats. Anesthesiology 55:369–375
Locke KW, Holtzman SG (1986) Behavioral effects of opioid peptides selective for mu or delta receptors. I. Morphine-like discriminative stimulus effects. J Pharmacol Exp Ther 238:990–996
Miksic S, Lal H (1977) Tolerance to morphine-produced discriminative stimuli and analgesia. Psychopharmacology 54:217–221
Millan MJ, Morris BJ, Herz A (1988) Antagonist induced opioid receptor up-regulation. I. Characterization of supersensitivity to selectivemu andkappa agonists. J Pharmacol Exp Ther 247:721–728
Morris BJ, Millan MJ, Herz A (1988) Antagonist-induced opioid receptor up-regulation. II. Regionally specific modulation of mu, delta, and kappa binding sites in rat brain revealed by quantitative autoradiography. J Pharmacol Exp Ther 247:729–736
Paronis CA, Holtzman, SG (1991) Increased analgesic potency of mu opioid agonists following continuous naloxone infusion in rats. J Pharmacol Exp Ther 259:582–589
Paronis CA, Holtzman SG (1992) Development of tolerance to the analgesic activity of mu agonists after continuous infusion of morphine, meperidine or fentanyl in rats. J Pharmacol Exp Ther 262:1–9
Picker MJ, Negus SS, Powell KR (1991) Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation. Psychopharmacology 103:129–135
Pugh SL, Boone MS, Emmett-Oglesby MW (1992) Tolerance, cross-tolerance and withdrawal in rats made dependent on diazepam. J Pharmacol Exp Ther 262:751–758
Sannerud CA, Young AM (1987) Environmental modification of tolerance to morphine discriminative stimulus properties in rats. Psychopharmacology 93:59–68
Schechter MD, Signs SA, Boja JW (1989) Stability of the stimulus properties of drugs over time. Pharmacol Biochem Behav 32:361–364
Shannon HE, Holtzman SG (1976) Evaluation of the discriminative stimulus effects of morphine in the rat. J Pharmacol Exp Ther 198:54–65
Tang AH, Collins RJ (1978) Enhanced analgesic effect of morphine chronic administration of naloxone in the rat. Eur J Pharmacol 47:473–474
Yoburn BC, Inturrisi CE (1988) Modification of the response to opioid and nonopioid drugs by chronic opioid antagonist treatment. Life Sci 42:1689–1696
Young AM, Mattox SR, Doty MD (1991a) Increased sensitivity to rate-altering and discriminative stimulus effects of morphine following continuous exposure to naltrexone. Psychopharmacology 103:67–73
Young AM, Kapitsopoulos G, Makhay MM (1991b) Tolerance to morphine-like stimulus effects of mu opioid agonists. J Pharmacol Exp Ther 257:795–805
Young AM, Masaki MA, Geula C (1992) Discriminative stimulus effects of morphine: effect of training dose on agonist and antagonist effects of mu opioids. J Pharmacol Exp Ther 261:246–257
Young AM, Sannerud CA, Steigerwald ES, Doty MD, Lipinski WJ, Tetrick LE (1990) Tolerance to morphine stimulus control: role of morphine maintenance dose. Psychopharmacology 102:59–67
Young AM, Steigerwald ES, Makhay MM, Kapitsopoulos G (1991c) Onset of tolerance to discriminative stimulus effects of morphine. Pharmacol Biochem Behav 39:487–493
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Paronis, C.A., Holtzman, S.G. Sensitization and tolerance to the discriminative stimulus effects of mu-opioid agonists. Psychopharmacology 114, 601–610 (1994). https://doi.org/10.1007/BF02244991
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DOI: https://doi.org/10.1007/BF02244991