The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Aug 1992
Randomized Controlled Trial Comparative Study Clinical TrialSubjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability.
The effects of orally administered placebo, diphenhydramine, lorazepam, methocarbamol and placebo were studied in volunteers with histories of recreational substance abuse including sedative/hypnotics. Placebo, diphenhydramine (100, 200 and 400 mg), lorazepam (1 and 4 mg) and methocarbamol (2.25 and 9 g) were tested in a randomized, double-blind crossover study using 14 subjects. Psychomotor and cognitive performance and subject- and observer-rated responses were measured daily before and for 5.5 hr after drug administration. ⋯ The present study clearly differentiated the behavioral and subjective profiles of diphenhydramine, lorazepam and methocarbamol. Consistent with its recognized low abuse liability, diphenhydramine produced fewer increases in measures of positive mood and more adverse effects. The considerable overlap in subjective effect measures of positive mood make further differentiation with respect to abuse liability difficult.
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J. Pharmacol. Exp. Ther. · Jul 1992
Spinal interactions between opioid and noradrenergic agonists in mice: multiplicativity involves delta and alpha-2 receptors.
The nature of the interaction between spinally administered opioid and alpha-2 agonists was investigated using the substance P behavioral test in mice. Morphine and agonists which more selectively activate mu or delta opioid receptors were co-administered intrathecally with direct and indirect acting adrenergic agonists norepinephrine, cocaine or clonidine and the behavioral responses to intrathecally coadministered substance P were evaluated. The ED50 values for agonists administered separately and concurrently were computed and drug interactions were evaluated using isobolographic analyses. ⋯ Both naloxone and idazoxan changed the antagonistic interaction between Tyr-D-Ala-NMe-Phe-Gly(ol) and clonidine to a multiplicative interaction. Neither antagonist blocked the multiplicative interaction between D-Pen2-D-Pen5-enkephalin and clonidine. These results suggest that: 1) interactions between opioid and adrenergic agonists in mouse spinal cord are mediated by delta and alpha-2 receptor subtypes; 2) the synergistic interaction between morphine and alpha-2 adrenergic agonists may involve action at delta opioid receptors; and 3) antagonist action on these drug interactions is complex.
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J. Pharmacol. Exp. Ther. · Apr 1992
Effects of buprenorphine and other opioid agonists and antagonists on alfentanil- and cocaine-reinforced responding in rhesus monkeys.
Rhesus monkeys self-administered a range of doses of either cocaine or alfentanil under a fixed-ratio 30, time out 45 sec schedule of i.v. drug delivery. Buprenorphine suppressed responding maintained by both cocaine and alfentanil; however, much larger doses of buprenorphine were required to suppress cocaine-reinforced as opposed to alfentanil-reinforced responding. ⋯ Increasing doses of the pure opioid antagonist quadazocine produced shifts to the right in the alfentanil rate-maintaining dose-effect curves but had no dose-related effect on behavior maintained by cocaine. The data suggest that buprenorphine suppresses drug-maintained responding through an agonist action but that alfentanil-maintained responding is uniquely sensitive to buprenorphine's effects.
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J. Pharmacol. Exp. Ther. · Mar 1992
Effects of ketamine on sensory perception: evidence for a role of N-methyl-D-aspartate receptors.
The chiral forms of ketamine were applied as probes for N-methyl-D-aspartate receptor-mediated neurotransmission in humans. Both enantiomers, in clinically relevant concentrations, displaced [3H]dizocilpine (MK 801) from specific binding sites (phencyclidine sites) in membrane fractions of brain homogenates. (S)-Ketamine was at least 4 times as potent as (R)-ketamine in this respect. In healthy volunteers, the most obvious effect of subanesthetic doses of both enantiomers was altered sensory perception. (S)-Ketamine was 4 times as potent as (R)-ketamine in reducing pain perception and in causing auditory and visual disturbances. ⋯ The ability to recall objects seen immediately before drug exposure was unaffected. The results are in accordance with the hypothesis that inhibition of sensory perception by ketamine in subanesthetic concentrations is due to N-methyl-D-aspartate receptor blockade. It is suggested that N-methyl-D-aspartate receptor-mediated transmission is involved in the processing of sensory information in the human brain.
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J. Pharmacol. Exp. Ther. · Feb 1992
Spinal opioid delta antinociception in the mouse: mediation by a 5'-NTII-sensitive delta receptor subtype.
Previous studies from our laboratory have indicated that i.c.v. pretreatment of mice with the novel, selective opioid delta receptor antagonists, [D-Ala2,Leu5,Cys6]enkephalin (DALCE) and naltrindole-5'-isothiocyanate (5'-NTII), differentially antagonized the direct antinociceptive effects of [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2]deltorphin II (DELT). These findings, and others, suggested the existence of subtypes of opioid delta receptors which could be classified as activated by DPDPE and DALCE sensitive (delta 1 receptor), or selectively activated by DELT and 5'-NTII sensitive (delta 2 receptor). The present study has extended these observations to the characterization of delta-mediated antinociception effects of DPDPE and DELT after i.t. administration in mice using pretreatment with DALCE and 5'-NTII in order to selectively antagonize the delta subtypes. ⋯ DPDPE, DELT and DALCE were 19.0 (12.9-28.1), 19.3 (16.1-23.1) and 2.0 (1.4-3.0) nmol. The delta antagonist, N,N-diallyl-Try-Aib-Aib-Phe-Leu-OH (ICI 174,864) (where Aib is alpha-aminoisobutyric acid) blocked the antinociceptive effects of DPDPE and DELT, but not those of i.t. morphine or [D-Ala2,NMPhe4,Gly-ol5]enkephalin (DAMGO), indicating that the observed antinociceptive effects of DPDPE and DELT were delta mediated. Pretreatment 24 hr before testing with graded doses of i.t. 5'-NTII blocked the i.t. antinociceptive effects of DPDPE and DELT, although at least a 10-fold higher dose of 5'-NTII was needed to produce equivalent antagonism of DPDPE.(ABSTRACT TRUNCATED AT 250 WORDS)