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NEUROPHARMACOLOGY

L-NAME (N-Nitro-L-Arginine Methyl Ester), a Nitric-Oxide Synthase Inhibitor, and WIN 55212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], a Cannabinoid Agonist, Interact to Evoke Synergistic Hypothermia

Department of Pharmaceutical Sciences (S.M.R.) and Department of Pharmacology (R.J.T., E.B.G., M.W.A.), Temple University School of Medicine, Philadelphia, Pennsylvania; and GlaxoSmithKline, Inc. (A.M.G.), Research Triangle Park, North Carolina

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 N-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.

Address correspondence to: Dr. Scott M. Rawls, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, PA 19140. E-mail: smrawls28{at}hotmail.com

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