The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jun 1997
Spinal infusion of N-methyl-D-aspartate antagonist MK801 induces hypersensitivity to the spinal alpha-2 agonist ST91 in the rat.
MK801 (MK), an N-methyl-D-aspartate (NMDA) receptor antagonist, attenuates tolerance to spinal opioids. Whether this applies to other G-protein-coupled receptor systems is unknown. This study examines the effects of continuous spinal MK on tolerance to the antinociceptive effect of continuous spinal infusion of the alpha-2 agonist ST91 (ST). ⋯ In conclusion, chronic spinal MK partially attenuates loss of sensitivity to chronic spinal ST. This supports the hypothesis that opioid- and adrenoceptor-induced tolerances are similarly modulated by the NMDA receptor. However, the increased sensitivity induced by MK alone suggests that NMDA receptor antagonism may not prevent the development of tolerance itself but may alter the expression of tolerance by inducing sensitivity via other alterations in cellular function.
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J. Pharmacol. Exp. Ther. · May 1997
Pharmacodynamics and tolerance development during multiple intravenous bolus morphine administration in rats.
Limited information is available about how the time course of the development of tolerance to morphine-induced antinociception is related to the kinetics of drug administration and disposition. The objectives of the present experiment were to characterize the rate and extent of tolerance development during the administration of multiple increasing i.v. bolus doses of morphine to rats, and to construct a pharmacokinetic-pharmacodynamic model of morphine tolerance. Morphine was administered according to two different treatment (TXT) regimens: a 12-hr TXT, in which a total morphine exposure of 24 mg/kg was administered in seven escalating doses, and a 13-day TXT, in which escalating doses of morphine were administered daily up to a maximum of 6 mg/kg. ⋯ Effect remained constant thereafter, with administration of the maximum dose of morphine for the remainder of the treatment period. A pharmacokinetic-pharmacodynamic model describing the development of tolerance during the 13-day TXT was constructed. The applicability of this model of tolerance to morphine-induced antinociception with different modes of administration is discussed.
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J. Pharmacol. Exp. Ther. · Apr 1997
Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine's respiratory, psychomotor and miotic effects.
Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. ⋯ In PMs, codeine's respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced-and hence codeine's pharmacodynamic effects were attenuated-in EMs of debrisoquin.
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J. Pharmacol. Exp. Ther. · Apr 1997
Clinical Trial Controlled Clinical TrialInhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability.
Enzymatic conversion of hydrocodone to hydromorphone is catalyzed by cytochrome P450 2D6, which is inactive in about 7% of Caucasians [poor metabolizers (PMs)] and can be inhibited by quinidine pretreatment in the remainder [extensive metabolizers (EMs)]. If hydromorphone, having a substantially higher mu-receptor affinity than hydrocodone, contributes importantly to the physiological and subjective effects of oral hydrocodone, then PMs should be less responsive to the same doses, and quinidine pretreatment should cause EMs to temporarily respond as PMs. ⋯ EMs and PMs were equally responsive to oral hydrocodone, and quinidine had no consistent effect on their responses, even though quinidine abolished the pre-existing metabolic differences in hydromorphone production, as measured in urine. These data suggest only a small role of hydromorphone in eliciting abuse-related responses to oral hydrocodone.
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J. Pharmacol. Exp. Ther. · Apr 1997
Antinociceptive effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, are enhanced by a cholecystokinin type B receptor antagonist, as revealed by noxiously evoked spinal c-Fos expression in rats.
The effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or with a selective cholecystokinin (CCK)B receptor antagonist (CI988) or CCK(A) receptor antagonist (devazepide), on carrageenin-induced spinal c-Fos expression were investigated. Spinal c-Fos expression was observed 90 min after intraplantar carrageenin (6 mg/150 microl saline), with Fos-like-immunoreactive neurons preferentially located in the superficial laminae of the spinal dorsal horn. Intravenous RB101 (10, 20 and 40 mg/kg) dose-dependently reduced the number of superficial Fos-like-immunoreactive neurons (r2 = 0.739, P < .0001), with 63 +/- 2% (P < .0001) reduction for the highest dose. ⋯ These results show that RB101 dose-dependently decreases carrageenin-evoked spinal c-Fos expression. In addition, the effectiveness of RB101 can be revealed by preadministration of the CCK(B) receptor antagonist CI988. Considering the weak opioid side effects obtained with RB101 treatment and the strong increase of its effects by the CCK(B) receptor antagonist, this type of drug combination could have promising therapeutic application in the management of pain in humans.