The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Feb 1997
Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat.
Neuropathic pain remains a significant clinical problem. Current understanding implicates the spinal cord dorsal horn N-methyl-d-aspartate (NMDA) receptor apparatus in its pathogenesis. Previous reports have described NMDA antagonist reduction of nerve injury-induced thermal hyperalgesia and formalin injection-related electrical activity. ⋯ In the nerve injury model, no supraspinal action was seen after intracerebroventricular injections of dextromethorphan and ketamine. NMDA antagonists by the spinal route appear to be useful therapeutic agents for chemically induced facilitated pain as well as nerve injury induced tactile allodynia. It is not known what accounts for the wide range of efficacies.
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J. Pharmacol. Exp. Ther. · Feb 1997
Early nociceptive events influence the temporal profile, but not the magnitude, of the tonic response to subcutaneous formalin: effects with remifentanil.
Injection of dilute formalin into the hindpaw produces brief (phase 1) and persistent (phase 2) nociceptive responses in the rat. We recently reported that ongoing peripheral nerve input is required for the expression of behavioral and cardiovascular responses during phase 2. Here we evaluated the contribution of central and peripheral sensitization mechanisms, generated during phase 1, to the magnitude and temporal profile of phase 2. ⋯ Continuous infusion (10 mg/kg/hr i.v.) of a peripherally acting opiate antagonist, naloxone methiodide, did not reduce the antinociception produced by remifentanil during phase 1 but almost completely reversed the delay in the onset and termination of phase 2. We conclude that central sensitization mechanisms during phase 1 do not influence the magnitude of phase 2. We also hypothesize that remifentanil interacts with peripheral opioid receptors to impede the formalin-evoked synthesis and/or release of proinflammatory compounds during phase 1 and thus delay phase 2.
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J. Pharmacol. Exp. Ther. · Dec 1996
Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain.
Male Sprague-Dawley rats were used to evaluate the antinociceptive properties of the selective N-type voltage-sensitive calcium channel (VSCC) blocker, SNX-111, when the compound is administered spinally by either bolus injection or continuous, constant-rate infusion into the subarachnoid space. SNX-111 produced significant, dose-dependent antinociceptive effects by suppressing both the acute (phase 1: ED50, 14 ng/hr) and tonic (phase 2: ED50, 0.82 ng/hr) phases of the formalin test when it was infused for 72 hr immediately before testing. Phase 2 nociceptive responses were suppressed by bolus injections of 100 ng SNX-111. ⋯ In rats with an experimentally induced painful peripheral neuropathy, intrathecal bolus injections of 30 to 300 ng SNX-111 blocked mechanical allodynia in a dose-dependent manner. Subacute administration of SNX-111 (1, 10 and 100 ng/hr) by continuous intrathecal infusion produced a reversible blockade of mechanical allodynia without apparent development of tolerance. These results show that: 1) selective N-type VSCC blockers are potent and efficacious antinociceptive agents when they are administered by the spinal route; 2) selective N-type VSCC blockers are effective in rat models of acute, persistent and neuropathic pain; and 3) N-type VSCCs play a significant role in the spinal processing of noxious somatosensory input.
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J. Pharmacol. Exp. Ther. · Nov 1996
N-cyclobutylmethyl analog of normorphinone, N-CBM-TAMO: a short-term opioid agonist and long-term Mu-selective irreversible opioid antagonist.
The antinociceptive and opioid binding properties of the N-cyclobutylmethyl analog of normorphinone, 14 alpha, 14' beta-[dithiobis[(2-oxo-2, 1-ethanediyl)imino]]bis[7,8-dihydro-N-(cyclobutylmethyl)-normor phinone] (N-CBM-TAMO) were investigated. This compound is a dimer, containing a disulfide capable of binding to thiol groups on the opioid receptor. Competition radioligand binding assays with bovine striatal membranes demonstrated that N-CBM-TAMO displayed a higher affinity for mu opioid receptors than for kappa and delta receptors. ⋯ N-CBM-TAMO at doses of 3 nmol and higher, which produced supermaximal short-term antinociception in the writhing test, produced a time- and dose-dependent long-term antagonism of U50,488 (trans)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate hydrate)-induced antinociception in a reversible manner, probably because of the development of tolerance. These in vivo data, together with the in vitro binding data, demonstrate that N-CBM-TAMO is a potent kappa agonist and at higher doses produces antinociception mediated by mu receptors. N-CBM-TAMO also produces long-term noncompetitive antagonism of antinociception mediated by mu opioid receptors.
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The dose-limiting toxicity of the chemotherapeutic agent vincristine is peripheral neuropathy, for which there is no established therapy. The amino acid glutamate has been proposed as a neuroprotectant for vincristine, but a full preclinical evaluation of its efficacy, safety and mechanism of action has been hampered by a lack of suitable animal models. We report the development of a Dark Agouti rat model of sensorimotor peripheral neuropathy, to investigate the neurotoxicity of cytotoxic drugs. ⋯ Our findings suggest that glutamate is likely to be a safe and effective neuroprotectant for patients receiving vincristine, and it warrants further clinical evaluation. The mechanism of this selective neuroprotection by glutamate remains to be elucidated. Our rat model may be of use in determining whether glutamate offers protection from other neurotoxic drugs.