DIFFERENTIAL-EFFECTS OF THE NOVEL ANALGESIC, S 12813-4, ON THE SPINAL RELEASE OF SUBSTANCE-P AND CALCITONIN-GENE-RELATED PEPTIDE-LIKE MATERIALS IN THE RAT

The possible inhibitory control by the novel analgesic S 12813-4 (3-(2-(4-phenylpiperazine-1-yl)-ethyl)-2-oxo-2,3-dihydrooxazolo(b)pyridine) of spinal neurones containing substance P (SP) and/or calcitonin gene-related peptide (CGRP) was assessed in vitro and in vivo in the rat. S 12813-4 (10 nM - 0.1 mM) did not affect the spinal release of CGRP-like material (CGRPLM) but inhibited in a concentration dependent manner the K+-evoked overflow of SP-like material (SPLM) from slices of the dorsal half of the rat lumbar enlargement. The inhibitory effect of 10 mu M S 12813-4 on SPLM release was not additive with that of Na (0.1 mM), and could be prevented by the alpha(2)-adrenoceptor antagonist idazoxan (10 mu M). Similarly, idazoxan (10 mu M) suppressed the inhibition by intrathecally administered S 12813-4 (10 mu M) of the spinal outflow of SPLM in halothane anaesthetized rats whose intrathecal space was perfused with an artificial cerebrospinal fluid. These data suggest that the analgesic effect of S 12813-4 might involve some alpha(2)-adrenoreceptor-mediated control of SPLM release within the spinal cord. Whether this control concerns SP-containing primary afferent fibres (presynaptic inhibition) or SP-containing interneurones and/or bulbo-spinal SP-ergic pathways (postsynaptic inhibition) deserves further investigations.