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 microM 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 microM). Similarly, idazoxan (10 microM) suppressed the inhibition by intrathecally administered S 12813-4 (10 microM) 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.
Collin
E
E
INSERM U. 288, Faculté de Médecine, Paris, France.
Frechilla
D
D
Pohl
M
M
Bourgoin
S
S
Mauborgne
A
A
Hamon
M
M
Cesselin
F
F
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D004146:Dioxanes / Q000494:pharmacology; D019329:Idazoxan; D066298:In Vitro Techniques; D007278:Injections, Spinal; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D000700:Analgesics; D004146:Dioxanes; D010080:Oxazoles; C088312:S 12813; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D009638:Norepinephrine; D019329:Idazoxan