RT Journal Article
SR Electronic
T1 <span class="sc">l</span>-NAME (<em>N</em><sup>ω</sup>-Nitro-<span class="sc">l</span>-Arginine Methyl Ester), a Nitric-Oxide Synthase Inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6<em>H</em>-pyrrolo[3,2,1<em>ij</em>]quinolin-6-one], a Cannabinoid Agonist, Interact to Evoke Synergistic Hypothermia
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 780
OP 786
DO 10.1124/jpet.103.054668
VO 308
IS 2
A1 Rawls, S. M.
A1 Tallarida, R. J.
A1 Gray, A. M.
A1 Geller, Ellen B.
A1 Adler, Martin W.
YR 2004
UL http://jpet.aspetjournals.org/content/308/2/780.abstract
AB Cannabinoids evoke profound hypothermia in rats by activating central CB1 receptors. Nitric oxide (NO), a prominent second messenger in central and peripheral neurons, also plays a crucial role in thermoregulation, with previous studies suggesting pyretic and antipyretic functions. Dense nitric-oxide synthase (NOS) staining and CB1 receptor immunoreactivity have been detected in regions of the hypothalamus that regulate body temperature, suggesting that intimate NO-cannabinoid associations may exist in the central nervous system. The present study investigated the effect of Nω-nitro-l-arginine methyl ester (l-NAME), a NO synthase inhibitor, on the hypothermic response to WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a selective cannabinoid agonist, in rats. WIN 55212-2 (1–5 mg/kg, i.m.) produced dose-dependent hypothermia that peaked 45 to 90 min post-injection. l-NAME (10–100 mg/kg, i.m.) by itself did not significantly alter body temperature. However, a nonhypothermic dose of l-NAME (50 mg/kg) potentiated the hypothermia caused by WIN 55212-2 (0.5–5 mg/kg). The augmentation was strongly synergistic, indicated by a 2.5-fold increase in the relative potency of WIN 55212-2. The inactive enantiomer of WIN 55212-2, WIN 55212-3 [S-(–)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-napthanlenyl) methanone mesylate] (5 mg/kg, i.m.), did not produce hypothermia in the absence or presence of l-NAME (50 mg/kg), confirming that cannabinoid receptors mediated the synergy. The present data are the first evidence that drug combinations of NOS blockers and cannabinoid agonists produce synergistic hypothermia. Thus, NO and cannabinoid systems may interact to induce superadditive hypothermia. The American Society for Pharmacology and Experimental Therapeutics