The novel analgesic, cizolirtine, inhibits the spinal release of substance P and CGRP in rats.
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.
INSERM U288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, Faculté de Médecine Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75634 Paris cedex 13, France.
S
S
Ballet
B
B
Aubel
A
A
Mauborgne
H
H
Poliénor
A
A
Farré
F
F
Cesselin
M
M
Hamon
A S
AS
Bourgoin
D019342:Acetic Acid / Q000008:administration & dosage; D000700:Analgesics / Q000494:pharmacology*; D000758:Anesthesia; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006221:Halothane / Q000494:pharmacology; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D011188:Potassium / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000187:drug effects* / Q000378:metabolism
D000700:Analgesics; D018685:Anesthetics, Inhalation; D011720:Pyrazoles; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide; D019342:Acetic Acid; D001241:Aspirin; D011188:Potassium; C075798:cizolirtine; D006221:Halothane