The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jul 1999
Biphasic modulation of visceral nociception by neurotensin in rat rostral ventromedial medulla.
A potential role for neurotensin in the rostral ventromedial medulla (RVM) in modulation of visceral nociceptive transmission was examined in this study. Microinjection of neurotensin (3-3000 pmol) into the RVM of awake rats produced a dose-dependent inhibition of the visceromotor response (VMR) to noxious colorectal distension (CRD) that lasted 30 to 120 min. Additionally, intra-RVM injection of neurotensin (300 pmol) significantly reduced the slope of the stimulus-response function to graded CRD (20-80 mm Hg), whereas the greatest dose of neurotensin (3000 pmol) completely inhibited the VMR at all intensities of CRD. ⋯ Additionally, intra-RVM injection of the neurotensin-receptor antagonist SR48692 (0.3-300 fmol) in naive animals produced dose-dependent inhibition of VMR to noxious CRD, whereas a lesser dose (0.03 fmol) enhanced the VMR. These data support a role for neurotensin in the RVM in biphasic modulation of visceral nociception. The results obtained with SR48692 suggest that endogenous neurotensin in the RVM modulates VMR to noxious CRD via a prominent interaction with neurotensin receptors that mediate facilitatory influences and a lesser interaction with neurotensin receptors that mediate masked inhibitory influences.
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J. Pharmacol. Exp. Ther. · Jul 1999
Gabapentin attenuates nociceptive behaviors in an acute arthritis model in rats.
In this study, we investigated the effectiveness of gabapentin (Neurontin), administered spinally with a microdialysis fiber, in reducing nociceptive behavioral responses induced by a knee joint inflammation model. This model is produced by injection of the knee joint with kaolin and carrageenan in rats. The resultant knee joint inflammation produces a secondary hyperalgesia to radiant heat applied to the hindpaw. ⋯ In animals with fully developed knee joint inflammation, gabapentin produced a reversal of heat hyperalgesia. The paw withdrawal latency responses and subjective pain scores were no longer significantly different from baseline, but joint circumference increases remained. These data suggest that gabapentin is an effective antinociceptive agent when administered either before or after induction of knee joint inflammation acting through a central neurogenic mechanism.
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J. Pharmacol. Exp. Ther. · Jul 1999
Randomized Controlled Trial Comparative Study Clinical TrialImpact of ethnic origin and quinidine coadministration on codeine's disposition and pharmacodynamic effects.
CYP2D6 is polymorphically distributed so that in poor metabolizers enzyme activity is missing. The goal of this study was to compare the pharmacokinetics and pharmacodynamics of codeine with and without quinidine between Caucasian and Chinese extensive metabolizers of debrisoquin. Nine Caucasians and eight Chinese subjects received in random, double blind fashion, on two occasions, codeine 120 mg. with placebo or with quinidine 100 mg. ⋯ The diminished production of morphine after quinidine was associated in the Caucasians, but not in the Chinese, with a marked reduction in codeine's effects (p <.01). In conclusion, Chinese produce less morphine from codeine, exhibit reduced sensitivity to that morphine, and therefore might experience reduced analgesic effect in response to codeine. In addition, quinidine induced inhibition of codeine O-demethylation is ethnically dependent with the reduction being greater in Caucasians.
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J. Pharmacol. Exp. Ther. · Jul 1999
Randomized Controlled Trial Clinical TrialCardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-methylenedioxymethamphetamine in humans.
The cardiovascular and neuroendocrine effects and pharmacokinetics of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") were assessed in a double-blind, randomized, crossover, and controlled (placebo and amphetamine) clinical trial. Eight men with experience in the recreational use of MDMA participated in four 10-h experimental sessions with a 1-week washout period. Single oral doses of 125 mg and 75 mg of MDMA, 40 mg of amphetamine, and placebo were given. ⋯ Amphetamine half-life was 15 h. Between 8 and 9% of the doses of MDMA appeared in plasma in the form of 3,4-methylenedioxyamphetamine. The important cardiovascular effects observed after MDMA administration in laboratory conditions at rest (increases of 40 mm Hg in systolic blood pressure and 30 beats/min in pulse rate) could be relevant in terms of toxicity in real-life conditions (e.g., crowded places and physical activity).
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J. Pharmacol. Exp. Ther. · Jul 1999
Randomized Controlled Trial Clinical TrialPeripheral effects of the kappa-opioid agonist EMD 61753 on pain and inflammation in rats and humans.
The objective of the present study was to evaluate the effects of EMD 61753 (asimadoline), a kappa-opioid receptor agonist with restricted access to the central nervous system, on postoperative pain in patients who underwent knee surgery and on nociceptive thresholds and inflammation in rats treated with Freund's complete adjuvant. Patients treated with EMD 61753 (10 mg p.o.) tended to report an increase in pain, as evaluated by a visual analog scale and by the time to the first request for and the total amount of supplemental analgesic medication. The global tolerability of EMD 61753 was assessed as significantly inferior to that of a placebo by the investigator. ⋯ EMD 61753 (1.6 mg)-induced analgesia was blocked by the peripheral opioid receptor antagonist naloxone methiodide (2.5-10 mg/kg s.c.) and by the kappa receptor antagonist nor-binaltorphimine (0.1 mg; i.pl.). In contrast, EMD 61753 (1.6 mg)-induced hyperalgesia and increases in paw volume and paw temperature were blocked neither by naloxone methiodide (10-40 mg/kg s.c.) nor by dizocilpine maleate (0.003-0.009 mg i.pl.), a N-methyl-D-aspartic acid receptor antagonist. These data show differentially mediated peripheral actions of EMD 61753: kappa-opioid receptor-induced analgesia and nonopioid, non-N-methyl-D-aspartic acid hyperalgesic and proinflammatory effects.