ABSTRACT
We assessed the possible influence of a neuropeptide FF analogue, 1DMe ([D-Tyr(1),(NMe)Phe(3)]neuropeptide FF), on the inhibitory action of endogenous and exogenous partial differential-opioid receptor agonists on K(+)-evoked [Met(5)]-enkephalin release from superfused rat spinal cord slices. 1DMe (0.1-10 microM) dose-dependently enhanced the increase in superfusate [Met(5)]-enkephalin content due to the peptidase inhibitors thiorphan (1 microM) and bestatin (20 microM), and prevented the reduction in [Met(5)]-enkephalin release due to stimulation of partial differential receptors by 1 microM deltorphin I. Because it had the same effects as partial differential-opioid receptor antagonists, 1DMe might act through the functional blockade of presynaptically located partial differential-opioid autoreceptors.
Subject(s)
Leucine/analogs & derivatives , Naltrexone/analogs & derivatives , Narcotic Antagonists , Oligopeptides/pharmacology , Spinal Cord/drug effects , Animals , Autoreceptors/antagonists & inhibitors , Dose-Response Relationship, Drug , Enkephalin, Methionine/metabolism , In Vitro Techniques , Leucine/pharmacology , Male , Naltrexone/pharmacology , Narcotic Antagonists/pharmacology , Potassium/pharmacology , Rats , Rats, Sprague-Dawley , Spinal Cord/metabolism , Thiorphan/pharmacologyABSTRACT
Although previous studies have established that cizolirtine (5-([(N,N-dimethylaminoethoxy)phenyl]methyl)-1-methyl-1H-pyrazol citrate) is a potent analgesic in rodents, its mechanism(s) of action remain(s) unclear. In vitro and in vivo approaches were used to assess whether cizolirtine could affect the spinal release of two pain-related neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP), in rats. Cizolirtine significantly reduced the K(+)-evoked overflow of both the SP-like material (SPLM; -25% at 0.1 microM--0.1 mM) and CGRPLM (-20% at 0.1--1.0 microM) from slices of the dorsal half of the lumbar enlargement of the spinal cord. Intrathecal perfusion in halothane-anaesthetized rats showed that local application of cizolirtine markedly diminished the spinal outflow of SPLM (up to -50% at 0.1 mM) but only marginally that of CGRPLM. Systemic administration of cizolirtine at an analgesic dose (80 mg/kg i.p.) also reduced spinal SPLM outflow (-50%) but not that of CGRPLM. Under both in vitro and in vivo conditions, idazoxan (10 microM) antagonized the effects of cizolirtine on SPLM and CGRPLM release, suggesting their mediation through alpha(2) adrenoceptors.
