sr-144528 and Hypothermia

Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide(AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22◦C, a moderate dose of LPS (25 - 100 μg kg−1 I.V.) induced a fall in body temperature with a nadir at ∼100 minpostinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 μg kg - 1 I.P.), by systemic TRPV1 antagonism with capsazepine(40mg kg−1 I.P.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kg−1 I.P.).However, CB1 receptor antagonism by rimonabant (4.6mg kg−1 I.P.) or SLV319 (15mg kg−1 I.P.)blocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered I.C.V. at a dose (4.6 μg) that was too low to produce systemic effects. The blockade of LPS hypothermia by I.C.V. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-α. In contrast to rimonabant,the I.C.V. administration of AEA (50 μg) enhanced LPS hypothermia. Importantly, I.C.V. AEAdid not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermo effector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Body Temperature Regulation; Brain; Camphanes; Capsaicin; Disease Models, Animal; Diterpenes; Endocannabinoids; Female; Hypothermia; Injections, Intraperitoneal; Injections, Intravenous; Injections, Intraventricular; Lipopolysaccharides; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Long-Evans; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Signal Transduction; Sulfonamides; Time Factors; TRPV Cation Channels

In contrast to the numerous reports on the pharmacological effects of Δ(9)-tetrahydrocannabinol (THC), the pharmacological activity of another substituent of Cannabis sativa, cannabichromene (CBC) remains comparatively unknown. In the present study, we investigated whether CBC elicits cannabinoid activity in the tetrad assay, which consists of the following four endpoints: hypomotility, antinociception, catalepsy, and hypothermia. Because cannabinoids are well documented to possess anti-inflammatory properties, we examined CBC, THC, and combination of both phytocannabinoids in the lipopolysaccharide (LPS) paw edema assay. CBC elicited activity in the tetrad that was not blocked by the CB(1) receptor antagonist, rimonabant. Moreover, a behaviorally inactive dose of THC augmented the effects of CBC in the tetrad that was associated with an increase in THC brain concentrations. Both CBC and THC elicited dose-dependent anti-inflammatory effects in the LPS-induced paw edema model. The CB(2) receptor, SR144528 blocked the anti-edematous actions of THC, but not those produced by CBC. Isobolographic analysis revealed that the anti-edematous effects of these cannabinoids in combination were additive. Although CBC produced pharmacological effects, unlike THC, its underlying mechanism of action did not involve CB(1) or CB(2) receptors. In addition, there was evidence of a possible pharmacokinetic component in which CBC dose-dependently increased THC brain levels following an i.v. injection of 0.3mg/kg THC. In conclusion, CBC produced a subset of behavioral activity in the tetrad assay and reduced LPS-induced paw edema through a noncannabinoid receptor mechanism of action. These effects were augmented when CBC and THC were co-administered.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Camphanes; Cannabinoids; Cannabis; Catalepsy; Dose-Response Relationship, Drug; Dronabinol; Hallucinogens; Hypothermia; Inflammation; Male; Mice; Mice, Inbred ICR; Motor Activity; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant

The present study investigated a potential role for cannabinoid CB(1) and CB(2) receptors in capsaicin-evoked hypothermia. Capsaicin (1 mg/kg, s.c.) caused rapid and significant hypothermia in rats. Pretreatment with SR 141716A (1, 2.5 and 5 mg/kg, i.p.), a CB(1) antagonist, or SR 144528 (1, 2.5 and 5 mg/kg, i.p.), a CB(2) antagonist, did not affect capsaicin-induced hypothermia. In separate experiments, the hypothermia caused by WIN 55212-2 (5 mg/kg, i.m.), a cannabinoid agonist, was not significantly altered by capsazepine (10 and 30 mg/kg, i.p.) or SB 366791 (2 mg/kg, i.p.), a novel TRPV1 antagonist. These data suggest that capsaicin causes hypothermia by a CB(1)- and CB(2)-independent mechanism, and that WIN 55212-2 causes hypothermia by a TRPV1-independent mechanism.

Topics: Anilides; Animals; Benzoxazines; Body Temperature; Calcium Channel Blockers; Camphanes; Capsaicin; Cinnamates; Hypothermia; Male; Morpholines; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; TRPV Cation Channels