The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Mar 2002
Effects of individual and concurrent stimulation of striatal D1 and D2 dopamine receptors on electrophysiological and behavioral output from rat basal ganglia.
Bilateral infusions of d-amphetamine into the rat ventral-lateral striatum (VLS) were previously shown to cause a robust behavioral activation that was correlated temporally with a net increase in firing of substantia nigra pars reticulata (SNpr) neurons, a response opposite predictions of the basal ganglia model. The current studies assessed the individual and cooperative contributions of striatal D1 and D2 dopamine receptors to these responses. Bilateral infusions into VLS of the D1/D2 agonist apomorphine (10 microg/microl/side) caused intense oral movements and sniffing, and an overall increase in SNpr cell firing to 133% of basal rates, similar to effects of d-amphetamine. ⋯ Selective stimulation of striatal D1 receptors by (+/-) 6-chloro-APB hydrobromide (SKF 82958; 10 microg/microl/side) + the D2 antagonist cis-N-(1-benzyl-2-methyl-pyrrolidin-3-yl)-5-chloro-2-methoxy-4-methyl-aminobenzamide (YM 09151-2; 2 microg/microl/side) caused a weak but sustained increase in oral movements and modestly increased SNpr cell firing, but neither response was of the magnitude observed with apomorphine. When the two agonists were infused concurrently, however, robust oral movements and sniffing again occurred over the same time period that a majority of SNpr cells exhibited marked, sometimes extreme and fluctuating, changes in firing (net increase, 117% of basal rates). These data confirm that concurrent striatal D1/D2 receptor stimulation elicits a strong motor activation that is correlated temporally with a net excitation rather than inhibition of SNpr firing, and reveal that D1 and D2 receptors interact synergistically within the striatum to stimulate both forms of output.
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J. Pharmacol. Exp. Ther. · Feb 2002
Effect of 2-(phosphono-methyl)-pentanedioic acid on allodynia and afferent ectopic discharges in a rat model of neuropathic pain.
Increased glutamate availability in the spinal cord and primary afferent nerves plays an important role in acute and chronic pain. Afferent ectopic discharges from the site of nerve injury constitute a source of abnormal sensory input to the spinal dorsal horn. The ectopic afferent activity is largely responsible for the development of hypersensitivity of dorsal horn neurons and neuropathic pain. ⋯ Furthermore, 2-PMPA dose-dependently attenuated the ectopic discharge activity of injured sciatic afferent nerves. At a dose of 100 mg/kg, 2-PMPA significantly inhibited the ectopic activity from 14.7 +/- 2.1 to 4.4 +/- 0.5 impulses/s without altering the conduction velocity of afferent nerves. Therefore, these data suggest that the antiallodynic effect of 2-PMPA may be mediated, at least in part, by inhibition of ectopic afferent discharges at the site of nerve injury.
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J. Pharmacol. Exp. Ther. · Feb 2002
Opioid receptor types selectively cointernalize with G protein-coupled receptor kinases 2 and 3.
Activation of G protein-coupled receptors (GPCRs) may bring about their disappearance from the cell membrane, and it is commonly accepted that G protein-coupled receptor kinases (GRKs) play a key function in this mechanism. Opioid receptors belong to the family of GPCRs and are substrates of GRKs. We examined the fate of delta- and mu-opioid receptors and GRK2 and 3 in living cells during the process of receptor sequestration, using laser scanning microscopy. ⋯ In analogous experiments with mu-opioid receptors fused to EGFP, we observed that receptor activation also discharges green fluorescent vesicles. In contrast to delta-receptors, mu-receptors failed to trigger accumulation of GRK2 or 3 at the membrane, and no cointernalization of mu-opioid receptors with GRK2 or 3 was observed. The results suggest that delta-opioid receptors, but not mu-receptors, cointernalize with GRK2 or 3.
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J. Pharmacol. Exp. Ther. · Feb 2002
Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.
Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. ⋯ The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.
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J. Pharmacol. Exp. Ther. · Jan 2002
Randomized Controlled Trial Clinical TrialEffects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial.
Methylnaltrexone, the first peripheral opioid receptor antagonist, has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. In previous human trials, we demonstrated that intravenous methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. We also observed that the compound decreased some of the morphine-induced troublesome subjective effects. ⋯ In addition, subcutaneous methylnaltrexone significantly decreased morphine-induced subjective rating changes. Pharmacokinetic data after subcutaneous drug injection were compared to the data obtained from previous intravenous and oral administrations. Our results suggest that subcutaneous methylnaltrexone may have clinical utility in treating opioid-induced constipation and reducing opioid-induced unpleasant subjective symptoms.