Involvement of N-methyl-D-aspartate receptors in nociception in the cyclophosphamide-induced vesical pain model in the conscious rat.
We previously showed that the intraperitoneal (i.p.) administration of 200mg/kg cyclophosphamide, an antitumoral agent, modified the behaviour of rats with cystitis induced by acrolein, a toxic urinary by-product of cyclophosphamide. This behaviour, (namely decreased breathing rate, closing of the eyes, and specific postures), was scored to indirectly assess the nociception elicited by the cystitis and to use this experimental model as a vesical pain model. Here we investigated the involvement of the N-methyl-D-aspartate (NMDA) receptors and thus of the excitatory amino acid system in this model. We administered dizocilpine (0.01 to 0.1mg/kg intravenously (i.v.) and 1 to 20 microg/rat intrathecally (i.t.)) and ketamine (5 and 10mg/kg i.v. and 50 to 1000 microg/rat i.t.), two non-competitive NMDA receptor antagonists that bind to the channel site, and AP-5 (0.01 to 1mg/kg i.v. and 20 to 500 microg/rat i.t), a competitive antagonist that binds to the glutamate site. Whichever the route of administration (i.v. or i.t.), dizocilpine dose-relatedly reduced the behavioural disorders induced by cyclophosphamide. Systemic ketamine also dose-dependently, though transiently, reduced the effects of cyclophosphamide, but ketamine i.t. and AP-5 i.v. and i.t. did not induce any reduction of these effects.These results (i) demonstrate that in the cyclophosphamide-induced vesical pain model NMDA receptors are involved in the nociception, as shown by the effects of dizocilpine and systemic ketamine, (ii) reveal marked differences in the data obtained with various NMDA receptor antagonists, possibly due to their physicochemical properties, to the animal pain model used, to the noxious stimulus applied or to any combination of these factors.
Méen
Murielle
M
EMI 9904 INSERM/UdA, Department of Physiology, Faculty of Pharmacy, B.P. 38, 63001 Clermont-Ferrand cedex 1, France. murielle.meen@voila.fr
Coudoré-Civiale
Marie-Ange
MA
Parry
Laurent
L
Eschalier
Alain
A
Boucher
Michel
M
D000171:Acrolein / Q000009:adverse effects; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects; D001522:Behavior, Animal; D003520:Cyclophosphamide / Q000009:adverse effects*; D003556:Cystitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D007278:Injections, Spinal; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D000171:Acrolein; D003520:Cyclophosphamide