Cannabinoids evoke profound
hypothermia in rats by activating central CB(1) 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 CB(1) 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(omega)-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.