Articles: narcotic-antagonists.
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Comparative Study
Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone.
Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. ⋯ Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.
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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 heptadecapeptide orphanin FQ has recently been shown to be the endogenous agonist for the orphan opioid-like receptor, LC132. The molecular evidence that LC132 and orphanin FQ are evolutionarily related to other opioid receptors and their ligands suggests that these proteins may also play a role in modulating opiate actions. ⋯ In addition to its antagonism of endogenous opioid antinociception, orphanin FQ dose-dependently (2.5-25 nmol) reverses systemic morphine antinociception (5 mg/kg, s.c.). Based on these data, we propose that orphanin FQ is a functional anti-opioid peptide.