European journal of pharmacology
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This study examined the influence of acute and repeated administration of the kappa-opioid receptor antagonist, nor-binaltorphimine, upon opioid-induced antinociception as measured by the tail-pressure test. A single intracerebroventricular (i.c.v.) injection of nor-binaltorphimine (30 micrograms) administered 1, 10 or 30 days prior to algesiometric testing prevented the analgesic effect of the kappa-opioid receptor agonist, (5 alpha, 7 alpha, 8 beta)-(-)-N- methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzenacet amide (U69593). The analgesic effect of the mu-opioid receptor agonist, [D-Ala2,N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO), and the delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), was not modified. ⋯ This treatment regimen also resulted in a long-lasting antagonism (e.g. 20 days) of U69593-induced analgesia. These data show that, depending on the treatment regimen employed, nor-binaltorphimine can function as a selective kappa-opioid receptor antagonist, or as an antagonist at multiple opioid receptor subtypes. Further, they demonstrate that nor-binaltorphimine functions as a long-lasting kappa-opioid receptor antagonist in vivo.
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Dermorphin, a specific mu 1-opioid receptor agonist, has been studied for its effects on the physiology of the rat hippocampal slice. Population responses in CA3 to threshold levels of stimulation from both the Schaffer collaterals and mossy fibers were markedly enhanced in the presence of 50-100 nM dermorphin, while CA1 responses to threshold Schaffer collateral stimulation were less effected. Responses at higher stimulus levels than threshold were negligibly responsive to dermorphin, although at 500 nM dermorphin all responses became epileptiform and in some slices spontaneous bursting erupted. [L-Ala2]Dermorphin, a biologically inactive dermorphin analogue, did not increase response amplitudes nor evoke epilepsy in the slice. 5 microM naloxone blocked the effect of dermorphin on Schaffer collateral and mossy fiber-evoked responses, though less effectively in the latter case. These data provide in vitro evidence to support in vivo observations that excessive mu-opioid receptor activation can be proconvulsant in the hippocampus, but that normally the receptors may function as facilitatory modulators of responses in the threshold range.