title: Capsaicin and nitric oxide synthase inhibitor interact to evoke a hypothermic synergy.
abstract: The present study investigated the effect of a drug combination of capsaicin and L-NAME on hypothermia in rats. Capsaicin administration (0.1, 0.25, 0.5, 1 and 2mg/kg, i.m.) caused a significant hypothermia. L-NAME (50mg/kg, i.p.), a nonspecific nitric oxide synthase (NOS) inhibitor, was ineffective. For combined administration, progressively increasing doses of capsaicin (0.1, 0.25, 0.5, 1 and 2mg/kg, i.p.) were given with a non-hypothermic dose of L-NAME (50mg/kg, i.p.). Experiments revealed that L-NAME (50mg/kg, i.p.) enhanced the hypothermic response to capsaicin (0.25, 0.5, 1, and 2mg/kg, i.m.). Comparison of the graded dose-effect curves for capsaicin alone and capsaicin plus L-NAME revealed a significant difference (P<0.05), thus indicating synergy for the drug interaction. To determine if L-NAME acted centrally, a fixed dose of L-NAME (1mg/rat, i.c.v.) was given with graded doses of capsaicin (0.25, 0.5, 1, and 2mg/kg, i.m.). L-NAME (1mg/rat, i.c.v.) only enhanced the hypothermia at a single dose of capsaicin (0.5mg/kg, i.m.). The super-additive hypothermia produced by the concurrent administration of capsaicin and L-NAME (50mg/kg, i.p.) is the first evidence of synergy for a drug combination of capsaicin and a NOS inhibitor. The synergy is apparent only when L-NAME is given systemically, thus indicating that the inhibition of peripheral NO production enhances the hypothermic response to capsaicin.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ding
authors.forename: Alan
authors.initials: A
authors.lastname: Cowan
authors.forename: Ronald
authors.initials: R
authors.lastname: Tallarida
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
mesh_terms: D000818:Animals; D048588:Benzoxazines; D001831:Body Temperature / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007035:Hypothermia / Q000139:chemically induced* / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009281:Naphthalenes / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000819:agonists
chemical_list: D048588:Benzoxazines; D004791:Enzyme Inhibitors; D009025:Morpholines; D009281:Naphthalenes; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D009569:Nitric Oxide; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D019001:Nitric Oxide Synthase; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester