title: Comparison of the effects of calmidazolium, morphine and bupivacaine on N-methyl-D-aspartate- and septide-induced nociceptive behaviour.
abstract: We have recently shown that spinal calmodulin inhibitors (W-7 and calmidazolium) dose-dependently inhibit the nociceptive reaction (biting, scratching, licking, BSL) evoked by intrathecal N-methyl-D-aspartate (NMDA) and septide, an agonist of the neurokinin (NK) NK1 receptor. To compare this effect with that induced by standard analgesics, we now report a study of the effects of calmidazolium (14420 nmol), bupivacaine (29-582 nmol) and morphine (26-260 nmol) when coadministered intrathecally with either NMDA (4 microg) or septide (0.5 microg). Calmidazolium had the highest potency for inhibiting septide-induced nociceptive behaviour, acting over a dose range of 34-130 nmol (dose eliciting a half-maximal response, ED50, 67 nmol) lower than that of bupivacaine [ED50 234 (115-475) nmol]. Only the highest dose of morphine (260 nmol) inhibited septide-evoked BSL [ED50=133 (69-255) nmol]. Higher doses of morphine could not be tested due to the appearance of an excitatory aversive reaction. Both calmidazolium [ED50=232 (138-388) nmol] and bupivacaine [ED50=123 (59-256) nmol] dose-dependently reduced NMDA-induced BSL reaching an almost maximal inhibition at the highest doses assayed (420 and 291 nmol, respectively). In contrast, morphine had less effect on NMDA-induced behaviour, inducing only a partial reduction of BSL even with the highest dose assayed (260 nmol). Overall, it can be concluded that the calmodulin inhibitor calmidazolium inhibits septide- and NMDA-evoked nociceptive behaviour with a potency and efficacy at least as high as those of morphine and bupivacaine.
authors.affiliation: Laboratorio de Farmacología, Departamento de Medicina, Facultad de Medicina, Oviedo, Asturias, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Alvarez-Vega
authors.forename: A
authors.initials: A
authors.lastname: Baamonde
authors.forename: M
authors.initials: M
authors.lastname: Gutiérrez
authors.forename: A
authors.initials: A
authors.lastname: Hidalgo
authors.forename: L
authors.initials: L
authors.lastname: Menéndez
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D002045:Bupivacaine / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced*; D010147:Pain Measurement; D010446:Peptide Fragments / Q000494:pharmacology; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000502:physiology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000700:Analgesics; D007093:Imidazoles; D010446:Peptide Fragments; D013373:Substance P; C031938:calmidazolium; D016202:N-Methylaspartate; D009020:Morphine; C054725:septide; D011761:Pyrrolidonecarboxylic Acid; D002045:Bupivacaine