The Journal of pharmacology and experimental therapeutics
-
J. Pharmacol. Exp. Ther. · Jan 1991
Interactions between the discriminative stimulus effects of mu and kappa opioid agonists in the squirrel monkey.
A series of mu and kappa opioid agonists with varying degrees of selectivity were evaluated for their agonist and antagonist effects in squirrel monkeys trained to discriminate either the selective mu agonist fentanyl or the selective kappa agonist U50,488 from water. In the fentanyl-trained monkeys, fentanyl, as well as the less selective mu agonists buprenorphine and (-)-metazocine, produced dose-dependent and complete substitution for the training stimulus. U50,488 produced neither agonist nor antagonist effects in the fentanyl-trained monkeys, but the less selective kappa agonists bremazocine and tifluadom generally produced either agonist or antagonist effects, depending on the monkey tested. ⋯ The inability of the selective mu agonist fentanyl and the selective kappa agonist U50,488 to antagonize each other's discriminative stimulus effects suggests that the stimulus effects mediated by mu and kappa opioid receptors in squirrel monkeys do not interact with a common biologic substrate. Rather, these results suggest that the stimulus effects mediated by mu and kappa receptors function independently of one another. Interactions involving the less selective mu agonists buprenorphine and (-)-metazocine, or the less selective kappa agonists bremazocine and tifluadom, can be explained on the basis of the low receptor selectivity of these drugs.
-
J. Pharmacol. Exp. Ther. · Dec 1990
An isobolographic analysis of the antinociceptive effect of systemically and intrathecally administered combinations of clonidine and opiates.
The antinociceptive interaction of opiate analgesics with clonidine was examined with the tail-flick and 55 degrees C hot plate tests. Male Sprague-Dawley rats received fixed ratios of clonidine to fentanyl, meperidine or morphine by i.v. and intrathecal injection. Data are expressed as percentage of maximal possible effect and the dose producing 50 percentage of maximal possible effect for each drug or drug combination is used to index potency. ⋯ This interaction may be additive or synergistic, depending on route of administration and the nociceptive test used. The timing of injections and pharmacokinetic factors may also influence the results. Moreover, these results suggest that the interaction between the opiate and alpha-2 adrenergic receptors occurs within the spinal cord.
-
J. Pharmacol. Exp. Ther. · Nov 1990
Comparative StudyAntagonist-induced up-regulation of the putative epsilon opioid receptor in rat brain: comparison with kappa, mu and delta opioid receptors.
We reported previously that in the presence of appropriate blocking agents [3H]ethylketocyclazocine selectively labels a non-mu, non-delta, non-kappa binding site with opioid receptor characteristics. We now report that chronic treatment with the opiate antagonist naltrexone dramatically increases the number of these binding sites in rat brain, as well as the number of mu, delta and kappa receptors. This finding further supports the concept that the [3H]ethylketocyclazocine site is an opioid receptor and previously reported evidence indicating that it might be the beta-endorphin-specific epsilon receptor that has been hypothesized to exist for some time. ⋯ In contrast, a maximal rate of kappa receptor up-regulation requires at least four naltrexone pellets and, therefore, the affinity of naltrexone for this site in vivo appears to be considerably lower than for the other sites. Unexpectedly, we found that the naltrexone-induced increase in binding to all four types of receptors continued to increase through 60 days of naltrexone exposure, the longest treatment period examined, and that the increases in receptor binding were linear with exposure time. This finding is contradictory to the generally held view that antagonist-induced opioid receptor up-regulation in brain increases asymptotically, leveling off after a relatively brief treatment period.
-
J. Pharmacol. Exp. Ther. · Aug 1990
Interaction of intrathecal morphine and ST-91 on antinociception in the rat: dose-response analysis, antagonism and clearance.
Physiological data suggest that the direct effect of spinal opiates as well as the activation of adrenergic bulbospinal pathways each results in a reduction in the gain of the stimulus response function in dorsal horn neurons. In its simplest form, this suggests the hypothesis that co-activation of spinal alpha2 and opioid receptors should be manifested as a synergistic interaction in which in its simplest form the net effect would be a product of the effect produced by either drug alone. To assess this hypothesis, rats were prepared with chronically implanted intrathecal (IT) catheters. ⋯ Confirmation of the synergistic nature of spinal opioid alpha 2 receptors was provided by the fact that IT injection of naloxone (90 nmol) or phentolamine (100 nmol) after IT injection of various combinations of morphine and ST-91 immediately and completely abolished the potentiating effect of the combination. The clearance of IT [3H]morphine from the thoracic and lumbar spinal cord was not changed in the presence of ST-91. These observations suggest a potent synergistic interaction between spinal mu and alpha 2 adrenergic receptor systems.
-
J. Pharmacol. Exp. Ther. · Feb 1990
Supersensitivity and changes in the active population of beta adrenoceptors in rat right atria in early sepsis.
We have investigated the effect of sepsis induced by cecal ligation and puncture on the chronotropic actions of beta adrenoceptor agonists on isolated right atria. The present findings show that right atria obtained from rats in an early stage of sepsis were supersensitive to the chronotropic actions of the beta-agonists, isoproterenol (ISO), fenoterol (FEN) and prenalterol (PREN). The supersensitivity to the chronotropic actions of ISO and FEN was much greater than that which developed to PREN. ⋯ The receptor subtypes mediating the responses to ISO, FEN and PREN by control and septic right atria were characterized by functional assays using selective beta-1 and beta-2 antagonists. The results showed that the chronotropic response produced by all three agonists on right atria obtained from control rats were mediated by beta-1 receptors. In contrast, the chronotropic actions of ISO and FEN on atria from septic rats were mediated by what appears to be beta-2 receptors and those of PREN by beta-1 receptors.