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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on November 10, 2003; DOI: 10.1124/jpet.103.054668

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Received for publication June 9, 2003.
Revised October 14, 2003.
Accepted for publication October 24, 2003.

L-NAME, a nitric oxide synthase inhibitor, and WIN 55212-2, a cannabinoid agonist, interact to evoke synergistic hypothermia

Scott M. Rawls 1*, Ronald J. Tallarida 2, Alex M. Gray 3, Ellen B. Geller 2, Martin W. Adler 2

1 Temple University School of Pharmacy 2 Temple University School of Medicine 3 GlaxoSmithKline

* Address correspondence to: E-mail: smrawls28{at}hotmail.com

Abstract

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 CNS. The present study investigated the effect of L-NAME, a NO synthase inhibitor, on the hypothermic response to WIN 55212-2, a selective cannabinoid agonist, in rats. WIN 55212-2 (1-5 mg/kg, i.m.) produced dose-dependent hypothermia that peaked 45-90 min post-injection. L-NAME (10-100 mg/kg, i.m.) by itself did not significantly alter body temperature. However, a non-hypothermic 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 (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 super-additive hypothermia.


Key words: L-NAME, WIN 55212-2, cannabinoid, hypothermia, nitric oxide, thermoregulation


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