Characteristics of dose-dependent antagonism by beta-funaltrexamine of the antinociceptive effects of intrathecal mu agonists.
Using rats with chronic i.t. catheters, dose-response curves were carried out using the hot plate (HP) test for a number of receptor-preferring opioids. The ordering of activity (i.t. ED50; nmol) on the HP was: (D-Ala2, N-Me-Phe4, Gly5-ol) enkephalin (DAMGO 0.5); sufentanil (0.4); and morphine (6.6). To assess the effects of pretreatment with the irreversible mu ligand beta-funaltrexamine (beta-FNA), rats received saline, 0.2, 2.0 or 20.0 nmol of beta-FNA. After 24 hr, base-line response latencies were not different from control animals. Dose-response curves for morphine, sufentanil and DAMGO were then obtained. Pretreatment with beta-FNA resulted in a concentration-dependent rightward shift in the agonist dose-response curves with the dose-ratio values of the respective doses of beta-FNA being for morphine: 3.5, 15.7, and 37.3; sufentanil: 1.2, 1.9, and 5.3; and DAMGO: 1.9, 4.0 and 7.3. The slopes of the agonist dose-response curves also displayed mild reductions in slope, the magnitude of which was dependent upon beta-FNA pretreatment concentrations. Testing at 6 days after beta-FNA treatment revealed a significant recovery of effect. beta-FNA (20 nmol, i.t.) had no effect on a just maximally effective dose of ST-91 (90 nmol, i.t.), an alpha-2 adrenergic agonist. beta-FNA (20 nmol, i.t.), but not 2.0 nmol resulted in a modest but significant reduction in the effect of the delta agonist DPLPE (120 nmol). These data are interpreted as supportive of the hypothesis that the mu-preferring ligands differ in the number of spinal receptors that must be occupied to produce a given antinociceptive effect (i.e., they differ in intrinsic efficacy).
Mjanger
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Department of Anesthesiology, Medical College of Wisconsin, Milwaukee.
Yaksh
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D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D005283:Fentanyl / Q000031:analogs & derivatives / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017450:Receptors, Opioid, mu; D013116:Spinal Cord / Q000187:drug effects; D017409:Sufentanil
D000700:Analgesics; D004745:Enkephalins; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009271:Naltrexone; C024524:beta-funaltrexamine; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; D017409:Sufentanil; D005283:Fentanyl