The novel analgesic, cizolirtine, inhibits the spinal release of substanceP and CGRP in rats

Although previous studies have established that cizolirtine (5-{[(N,N-dimet hylaminoethoxy)phenyl]methyl}-I-methyl-1H-pyrazol citrate) is a potent anal gesic in rodents, its mechanism(s) of action remain(s) unclear. In vitro an d in vivo approaches were used to assess whether cizolirtine could affect t he spinal release of two pain-related neuropeptides, substance P (SP) and c alcitonin gene-related peptide (CGRP), in rats. Cizolirtine significantly r educed the K+-evoked overflow of both the SP-like material (SPLM; -25% at 0 .1 muM-0.1 mM) and CGRPLM (-20% at 0.1-1.0 muM) from slices of the dorsal h alf of the lumbar enlargement of the spinal cord. Intrathecal perfusion in halothane-anaesthetized rats showed that local application of cizolirtine m arkedly diminished the spinal outflow of SPLM (up to -50% at 0.1 mM) but on ly 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 (1 0 muM) antagonized the effects of cizolirtine on SPLM and CGRPLM release, s uggesting their mediation through alpha (2) adrenoceptors. (C) 2001 Elsevie r Science Ltd. All rights reserved.