CB₁ Receptors in the Preoptic Anterior Hypothalamus Regulate WIN 55212-2 [(4,5-Dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-Induced Hypothermia

Abstract

The present study investigated the effect of the selective cannabinoid agonist, WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], on body temperature. WIN 55212-2 (1, 2.5, 5, and 10 mg/kg, i.m.) induced hypothermia in a dose-dependent manner. The peak hypothermia occurred 60 to 180 min postinjection. Body temperature was still suppressed 5 h after the injection of the highest dose of WIN 55212-2. The selective hypothermia. Neither SR141716A nor SR144528 alone altered body temperature. WIN 55212-2 (1-30 g/l) injected directly into the preoptic anterior hypothalamic nucleus (POAH) induced hypothermia in an immediate and dose-dependent fashion. The hypothermia produced by intra-POAH injection of WIN 55212-2 was brief, with body temperature returning to baseline 60 min postinjection. SR141716A (5 mg/kg, i.m.) abolished the hypothermia induced by intra-POAH injection of WIN 55212-2 (30 g/l), indicating that CB 1 receptors in the POAH mediated the hypothermia. The present results confirm the idea that CB 1 receptors mediate the hypothermic response to cannabinoid agonists. Moreover, the present data suggest that 1) the POAH is the central locus for thermoregulation, and 2) CB 1 receptors within the POAH are the primary mediators of cannabinoid-induced hypothermia.

Improgan-induced hypothermia: A role for cannabinoid receptors in improgan-induced changes in nociceptive threshold and body temperature

“…1E), which supports a brain CB 1 -mediated mechanism for this effect (Pertwee, 2001). Systemic dosing with rimonabant has been shown to block hypothermia induced by either systemic, ivt or intracerebral cannabinoid administration (Rinaldi-Carmona et al, 1994;Rawls et al, 2002), but we are unaware of any previous studies documenting the ability of ivt rimonabant to block hypothermia produced by ivt cannabinoids.…”

“…Earlier results suggest that either WIN-55,212-2 or CP-55,940 might serve as a suitable cannabinoid control drug for inducing hypothermia. (Lichtman et al, 1996;Rawls et al, 2002). However, pilot studies with ivt WIN 55,212-2 (20μg) failed to elicit significant hypothermia between 3-30 min following drug administration (data not shown).…”

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

“…27 Similarly, WIN55212-2, which was used as a CB1-receptor agonist in this study, induced profound hypothermia and was blocked by pretreatment with SR141716A (3 and 10 mg kg À1 ). 28 With Compound-1, it significantly antagonized CB1-agonist-induced hypothermia in mice only treated with a dose of 100 mg kg À1 (Figure 4). Based on these results, it can be concluded that even though pharmacokinetic properties of Compound-1 are more favorable than those of SR141716A, its site of action can be limited to peripheral CB1 receptors especially at low doses because of its low BBB permeability.…”

Dose-Related Differences in the Regional Pattern of Cannabinoid Receptor Adaptation and in Vivo Tolerance Development to Δ9-Tetrahydrocannabinol

“…For example, cannabinoid-mediated antinociception involves the PAG (Lichtman et al, 1996), whereas hypothermia involves the POA (Rawls et al, 2002). Motor behavior involves CB 1 receptors in the basal ganglia and cerebellum.…”