Antinociception: mechanistic studies on the action of MD-354 and clonidine. Part 1. The 5-HT3 component.
MD-354 (m-chlorophenylguanidine) is a 5-HT3/alpha2B-adrenoceptor ligand. Both receptors play a role in antinociception. In the mouse tail-flick assay, subcutaneously administered MD-354 was inactive as an analgesic. However, a combination of an inactive dose of clonidine (0.25 mg/kg) with an inactive dose of MD-354 (6 mg/kg) produced a substantial antinociceptive effect (maximal possible effect=66%). Considering the 5-HT3 receptor partial agonist properties of MD-354, the analgesia enhancing effect of MD-354 on clonidine might be associated, at least in part, with its 5-HT3 receptor agonist or antagonist activity. Combinations of an inactive dose of clonidine (0.25 mg/kg) with 5-HT3 receptor antagonists (tropisetron, zacopride and ondansetron) were examined. Saline-like doses of tropisetron, zacopride and ondansetron significantly enhanced the antinociceptive effect of clonidine (combinations: maximal possible effect=86%, 82% and 79% respectively), suggesting that MD-354 may enhance the analgesic actions of clonidine, at least in part, through a 5-HT3 receptor antagonist mechanism.
Dukat
Magorzata
M
Department of Medicinal Chemistry, School of Pharmacy, Box 980540 Virginia Commonwealth University, Richmond, VA 23298-0540, USA. mdukat@hsc.vcu.edu
Wesołowska
Anna
A
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006146:Guanidines / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects; D017294:Ondansetron / Q000494:pharmacology; D010146:Pain / Q000517:prevention & control; D010147:Pain Measurement; D044406:Receptors, Serotonin, 5-HT3 / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D000077526:Tropisetron
D000700:Analgesics; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D006146:Guanidines; D007211:Indoles; D044406:Receptors, Serotonin, 5-HT3; D012702:Serotonin Antagonists; C495409:m-chlorophenylguanidine; D017294:Ondansetron; D000077526:Tropisetron; C055971:zacopride; D003000:Clonidine