Baclofen and NOS inhibitors interact to evoke synergistic hypothermia in rats.
Our laboratory recently demonstrated that a drug combination of baclofen and L-NAME, a nonspecific nitric oxide synthase (NOS) inhibitor, evokes synergistic hypothermia in rats. These data are the first demonstration of synergy between a GABA agonist and NOS inhibitor. While the hypothermic synergy suggests a role for NOS in baclofen pharmacology, it is unclear whether the super-additive hypothermia is specific for baclofen and L-NAME or extends to drug combinations of baclofen and other NOS inhibitors. The site of action (central or peripheral) and isoforms of NOS that mediate the synergy are also unknown. Here, we confirm the hypothermic synergy with additional data and discuss potential mechanisms of the drug interaction. Baclofen (2.5, 3.5, 5 and 7.5 mg/kg, i.p.) was administered to rats by itself or with 7-nitroindazole (7-NI), a neuronal NOS inhibitor. 7-NI (10 mg/kg, i.p.) did not affect body temperature. For combined administration, 7-NI (10 mg/kg, i.p.) increased the relative potency of baclofen (F=18.9, P<0.05). The present data validate the hypothermic synergy caused by the drug combination of baclofen and L-NAME and implicate nNOS in the synergy. In a context broader than thermoregulation, NO production and transmission may play an important role in baclofen pharmacology.
Rawls
Scott M
SM
Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA 19140, USA. scott.rawls@temple.edu
Jacobs
Kyle
K
Tallarida
Ronald J
RJ
D000818:Animals; D019540:Area Under Curve; D001418:Baclofen / Q000633:toxicity*; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity; D018755:GABA Agonists / Q000633:toxicity*; D007035:Hypothermia / Q000139:chemically induced* / Q000201:enzymology / Q000503:physiopathology; D007191:Indazoles / Q000633:toxicity; D007274:Injections, Intraperitoneal; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis
D004791:Enzyme Inhibitors; D018755:GABA Agonists; D007191:Indazoles; D019001:Nitric Oxide Synthase; D001418:Baclofen; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester