-
[show abstract]
[hide abstract]
ABSTRACT: Level pressing by squirrel monkeys was maintained under a fixed-ratio 30 schedule of food presentation. The response rate-decreasing effects of meperidine and morphine were examined alone and in combination with several doses of the irreversible, mu-selective opioid antagonist beta-funaltrexamine and the reversible, opioid antagonist naltrexone. beta-Funaltrexamine alone decreased response rates to greater than 50% of control at all doses in two of the four monkeys and at the highest dose in one monkey. In the monkeys in which beta-funaltrexamine decreased rates, beta-funaltrexamine either did not shift the meperidine or the morphine dose-effect curve or it shifted these curves to the left. In the monkeys in which beta-funaltrexamine alone did not decrease rates, it shifted the meperidine and the morphine dose-effect curves to the right. Naltrexone also shifted both the meperidine and morphine dose-effect curves rightward, although not in a dose-dependent manner. These data suggest that the rate-decreasing effects of meperidine and morphine in squirrel monkeys are altered by beta-funaltrexamine and naltrexone in a similar manner, providing additional evidence that the rate-decreasing effects of both meperidine and morphine are mediated by mu-opioid receptors.
Drug and Alcohol Dependence 06/1997; 45(3):197-206. · 3.38 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study was designed to characterize the degree of cross-tolerance between the response rate-decreasing effects of morphine and three mu opioids with varying relative intrinsic efficacies at the mu receptor, buprenorphine, butorphanol and fentanyl, and a non-opioid (+) amphetamine, in a behavioral-tolerance paradigm. Lever pressing of rats was maintained by a fixed-ratio 20-schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine in separate groups of rats administered morphine either before (pre-session) or after (post-session) experimental sessions. Each of the mu opioids and the non-opioid (+)-amphetamine dose-dependently decreased response rates. In the pre-session group, daily administration of morphine shifted the morphine dose-effect curve 0.33 log unit rightward, indicating that tolerance had developed, and shifted the butorphanol dose-effect curve 0.96 log unit rightward. Daily pre-session administrations of morphine did not shift the dose-effect curves for buprenorphine, fentanyl, or (+)-amphetamine. In the post-session group, daily administration of morphine did not shift the morphine, butorphanol, buprenorphine, fentanyl, or (+)-amphetamine dose-effect curves. These data suggest that pharmacological variables, such as the drug's relative intrinsic efficacy at the mu receptor, can play a role in behavioral tolerance and cross-tolerance.
Behavioural pharmacology 06/1996; 7(3):228-236. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Studies have shown that the noradrenergic system is involved in the analgesic effects of opioids and in the expression and development of physical signs of opioid withdrawal. The purpose of the present experiment was to determine if the noradrenergic system was involved in the discriminative effects of morphine in rats trained to discriminate 5.6 mg/kg morphine from saline under a fixed-ratio schedule of food presentation. A range of doses of morphine (0.3-10.0 mg/kg) produced dose-dependent increases in morphine-appropriate responding without substantial decreases in response rate. Several experiments were conducted to determine whether a number of noradrenergic agonists and antagonists 1) substitute for morphine or 2) alter the discriminative-stimulus effects of morphine when administered concurrently. The alpha 2 agonist clonidine (0.003-0.1 mg/kg), the alpha 1 antagonist prazosin (0.1-10.0 mg/kg), the alpha 2 antagonist yohimbine (0.1-10.0 mg/kg), the beta 2 agonist salbutamol (0.03-10.0 mg/kg), and the beta antagonist propranolol (1.0-10.0 mg/kg), neither substituted for morphine nor altered the discriminative-stimulus effects of morphine when administered in combination. These data suggest that the noradrenergic system is not involved in the discriminative-stimulus effects of 5.6 mg/kg morphine in rats.
Pharmacology Biochemistry and Behavior 05/1996; 53(4):979-86. · 2.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The present study was designed to characterize the degree of cross-tolerance between the response rate-decreasing effects of morphine and three mu opioids with varying relative intrinsic efficacies at the mu receptor, buprenorphine, butorphanol and fentanyl, and a non-opioid (+)-amphetamine, in a behavioral-tolerance paradigm. Lever pressing of rats was maintained by a fixed-ratio 20 schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine in separate groups of rats administered morphine either before (pre-session) or after (post-session) experimental sessions. Each of the mu opioids and the non-opioid (+)-amphetamine dose-dependently decreased response rates. In the pre-session group, daily administration of morphine shifted the morphine dose-effect curve 0.33 log unit rightward, indicating that tolerance had developed, and shifted the butorphanol dose-effect curve 0.96 log unit rightward. Daily pre-session administrations of morphine did not shift the dose-effect curves for buprenorphine, fentanyl, or (+)-amphetamine. In the post-session group, daily administration of morphine did not shift the morphine, butorphanol, buprenorphine, fentanyl, or (+)-amphetamine dose-effect curves. These data suggest that pharmacological variables, such as the drug's relative intrinsic efficacy at the mu receptor, can play a role in behavioral tolerance and cross-tolerance.
(C) Lippincott-Raven Publishers.
Behavioural Pharmacology 04/1996; 7(3). · 2.72 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of the present experiment was to assess the degree of tolerance and cross-tolerance to the response rate-decreasing effects of opioids with different degrees of intrinsic efficacy at the mu receptor. The mu opioids included buprenorphine, etorphine, l-methadone, morphine, and sufentanil. Lever pressing of squirrel monkeys was maintained by a fixed-ratio (FR) 30 schedule of food presentation, and dose-effect curves for each drug were obtained prior to, during, and after daily administrations of morphine. Each of the mu opioids, and the non-opioid pentobarbital, dose-dependently decreased response rates. Daily administration of morphine produced approximately a 0.9 log unit rightward shift in the morphine dose-effect curve. During this chronic-morphine phase of the experiment, the dose-effect curve for pentobarbital was not shifted consistently, whereas the dose-effect curves for buprenorphine, etorphine, l-methadone, and sufentanil were shifted between 0.4 and 0.6 log unit to the right. Therefore etorphine, l-methadone and sufentanil, mu opioids thought to have high intrinsic efficacy, and buprenorphine, a mu opioid thought to have low intrinsic efficacy, all produced a smaller degree of cross-tolerance than that observed for morphine, and pentobarbital, a non-opioid, did not produce cross-tolerance.
Behavioural pharmacology 01/1996; 6(8):776-784. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The stimulus effects of selective, high efficacy mu opioids and mixed action opioids with varying degrees of intrinsic efficacy at the mu receptor were examined in pigeons trained to discriminate between saline and either 0.056 (low) or 0.18 (high) mg/kg of fentanyl. The stimulus profiles produced by the various opioids could be separated into three groups: 1) opioids that substituted completely for both training doses of fentanyl, with steep slopes and little interanimal differences in the lowest dose (lowest discriminable dose) that produced complete substitution (fentanyl, morphine and l-alpha-acetylmethadol); 2) opioids that substituted completely for the low training dose and produced high levels of substitution for the high training dose, with relatively shallow slopes and interanimal differences in the lowest discriminable dose (butorphanol, buprenorphine, ethylketocyclazocine, ketocyclazocine, proxorphan, (-)-pentazocine and (-)-metazocine); and 3) opioids that substituted completely for the low training dose, with relatively shallow slopes and large interanimal differences in the lowest discriminable dose. Each of these opioids also antagonized the high-dose fentanyl stimulus with large interanimal differences in the lowest antagonist dose (nalbuphine, nalorphine, (-)-cyclorphan, (-)-cyclazocine, (-)-n-ally-normetazocine and levallorphan). These patterns of substitution and antagonism most likely reflect differences in the intrinsic efficacy of these drugs at the mu receptor, with low intrinsic efficacy associated with shallow dose-effect functions, large interanimal differences in the drug's lowest discriminable dose and low levels of substitution for the high-dose fentanyl stimulus. During antagonism tests with naloxone, two patterns were observed: 1) opioids against which naloxone had apparent pA2 values of approximately 7.0, with little interanimal differences and with the slopes of the Schild plots approximating -1.0 (fentanyl and morphine) and 2) opioids against which naloxone had apparent pA2 values an order of magnitude higher, with large interanimal differences and with the slopes of Schild plots being relatively shallow (butorphanol, nalbuphine, nalorphine and levallorphan). The present findings emphasize the importance of training dose, intrinsic efficacy and interanimal differences when analyzing drug discrimination data.
Journal of Pharmacology and Experimental Therapeutics 09/1993; 266(2):756-67. · 3.83 Impact Factor
