Differential influence of two serotonin 5-HT3 receptor antagonists on spinal serotonin-induced analgesia in rats.
We tested the antinociceptive effect of intrathecal (i.t.) administration of 5-HT3 and the 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), in rats submitted to a mechanical noxious stimulus and the influence of the 5-HT3 receptor selective antagonists, tropisetron and granisetron. Both 5-HT and mCPBG (0.01, 0.1, 1, 10, 20 micrograms/rat) produced a significant dose-dependent antinociception. The lowest active doses were 0.1 and 1 microgram for 5-HT and mCPBG, respectively. The effect, observed with 20 micrograms, was significantly lower with mCPBG (+33 +/- 6%) than with 5-HT (+63 +/- 7%). For 5-HT-induced antinociception, the minimal inhibitory doses were 0.001 micrograms/rat for tropisetron and 10 micrograms/rat for granisetron. In contrast, the same doses of the two antagonists (from 0.1 microgram/rat) similarly inhibited the effect of mCPBG. This study provides evidence that contrary to tropisetron, doses of granisetron able to inhibit the effect of a 5-HT3 receptor agonist failed to reduce that of 5-HT. This demonstrates a heterogeneity between 5-HT3 receptor antagonists and questions the true involvement of these receptors in spinal 5-HT-induced antinociception.
Bardin
L
L
Equipe NPPUA, Laboratoire de Pharmacologie Médicale, Faculté de Médecine, Clermont-Ferrand, France.
Jourdan
D
D
Alloui
A
A
Lavarenne
J
J
Eschalier
A
A
D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017829:Granisetron / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D012684:Sensory Thresholds / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects; D000077526:Tropisetron
D001645:Biguanides; D017829:Granisetron; D007211:Indoles; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D000077526:Tropisetron; C065734:1-(3-chlorophenyl)biguanide