The Journal of pharmacology and experimental therapeutics
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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.