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Tolerance and cross-tolerance to the response rate-decreasing effects of µ opioids in morphine-maintained squirrel
C.E. Hughes1, M.J. Picker, L.A. Dykstra
1Department of Psychology, University of North Carolina, Chapel Hill, NC 27599-3270, USA.
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.
Insights
This study investigated opioid tolerance and cross-tolerance using different mu opioid drugs in squirrel monkeys. Results show varying degrees of cross-tolerance among opioids, with morphine-induced tolerance being most significant.
Area of Science:
- Pharmacology
- Neuroscience
- Drug Addiction Research
Background:
- Opioid receptors, particularly the mu receptor, are key targets for pain management and addiction.
- Understanding tolerance and cross-tolerance is crucial for developing effective opioid therapies and managing addiction.
Purpose of the Study:
- To quantify the tolerance and cross-tolerance to the effects of various mu-opioid agonists with differing intrinsic efficacies.
- To compare the development of tolerance to morphine with cross-tolerance to other opioids and a non-opioid.
Main Methods:
- Squirrel monkeys were trained on a fixed-ratio (FR) 30 schedule for food reinforcement.
- Dose-effect curves were established for buprenorphine, etorphine, l-methadone, morphine, sufentanil, and pentobarbital.
- Chronic daily morphine administration was used to induce tolerance, and subsequent dose-effect curves were analyzed.
Main Results:
- Daily morphine administration caused a significant rightward shift (0.9 log units) in the morphine dose-effect curve, indicating tolerance.
- Cross-tolerance to other mu-opioids (buprenorphine, etorphine, l-methadone, sufentanil) ranged from 0.4 to 0.6 log units.
- The non-opioid pentobarbital showed inconsistent shifts, suggesting a lack of cross-tolerance.
Conclusions:
- All tested mu-opioids, regardless of intrinsic efficacy, induced less cross-tolerance than morphine itself.
- Pentobarbital did not induce significant cross-tolerance, differentiating it from mu-opioid effects.
- Findings highlight the complex mechanisms of opioid tolerance and cross-tolerance at the mu receptor.