sb-366791 and Hypothermia

In recent years, there has been increasing interest in hypothermia induced by paracetamol for therapeutic purposes, which, in some instances, has been reported as a side effect. Understanding the mechanism by which paracetamol induces hypothermia is therefore an important question. In this study, we investigated whether the novel metabolite of paracetamol, N-(4-hydroxyphenyl)arachidonylamide (AM404), which activates the cannabinoid (CB) and transient receptor potential vanilloid-1 (TRPV1) systems, mediates the paracetamol-induced hypothermia. The hypothermic response to 300 mg/kg paracetamol in CB(1) receptor (CB(1)R) and TRPV1 knockout mice was compared to wild-type mice. Hypothermia induced by paracetamol was also investigated in animals pretreated with the CB(1)R or TRPV1 antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperdinyl-1H-pyrazole-3-carboxamide trifluoroacetate salt (AM251) or 4'-chloro-3-methoxycinnamanilide (SB366791), respectively. In CB(1)R or TRPV1 knockout mice, paracetamol induced hypothermia to the same extent as in wild-type mice. In addition, in C57BL/6 mice pretreated with AM251 or SB366791, paracetamol induced hypothermia to the same extent as in control mice. AM404 failed to induce hypothermia at pharmacological doses. Inhibition of fatty acid amide hydrolase (FAAH), which is involved in the metabolism of paracetamol to AM404, did not prevent the development of hypothermia with paracetamol. Paracetamol also induced hypothermia in FAAH knockout mice to the same extent as wild-type mice. We conclude that paracetamol induces hypothermia independent of cannabinoids and TRPV1 and that AM404 does not mediate this response. In addition, potential therapeutic value of combinational drug-induced hypothermia is supported by experimental evidence.

Topics: Acetaminophen; Amidohydrolases; Anilides; Animals; Arachidonic Acids; Cannabinoids; Cinnamates; Hypothermia; Hypothermia, Induced; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Piperidines; Pyrazoles; Receptor, Cannabinoid, CB1; TRPV Cation Channels

AM 404 inhibits endocannabinoid uptake and enhances the cannabinoid CB(1)-mediated effects of endogenous cannabinoids. Accumulating evidence also suggests that AM 404 acts at sites other than the endocannabinoid system. One site is the transient receptor potential vanilloid 1 cation channel (TRPV1). A useful endpoint for discriminating between TRPV1- or CB(1)-mediated effects of AM 404 is hypothermia. This is because TRPV1 or CB(1) receptor activation produces a significant hypothermia in rats. The present study investigated the effects of AM 404 (1, 5, 10 and 20 mg/kg, i.p.) on body temperature in rats and the involvement of TRPV1 and CB(1) receptors in the effects of AM 404. Doses of 10 and 20 mg/kg of AM 404 produced significant hypothermia. Pre-treatment with capsazepine (30 mg/kg, i.p.) blocked the hypothermia caused by 10 and 20 mg/kg of AM 404. Pre-treatment with SB 366791 (2 mg/kg, i.p.), a new TRPV1 antagonist, also abolished the hypothermia evoked by AM 404 (20 mg/kg, i.p.). In contrast, pre-treatment with SR 141716A (Rimonabant), a CB(1) antagonist, or AA-5-HT, a fatty acid amide hydrolase (FAAH) blocker, did not affect AM 404-evoked hypothermia. The present data demonstrate that AM 404 evokes a significant hypothermia in rats that is dependent on TRPV1 receptor activation.

Topics: Amidohydrolases; Anilides; Animals; Arachidonic Acids; Body Temperature; Capsaicin; Cinnamates; Endocannabinoids; Hypothermia; Male; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Rimonabant; TRPV Cation Channels

The TRPV1 capsaicin receptor is a non-selective cation channel localized in the cell membrane of a subset of primary sensory neurons and functions as an integrator molecule in nociceptive/inflammatory processes. The present paper characterizes the effects of SB366791, a novel TRPV1 antagonist, on capsaicin-evoked responses both in vitro and in vivo using rat models. SB366791 (100 and 500 nM) significantly inhibited capsaicin-evoked release of the pro-inflammatory sensory neuropeptide substance P from isolated tracheae, while it did not influence electrically induced neuropeptide release. It also decreased capsaicin-induced Ca2+ influx in cultured trigeminal ganglion cells in a concentration-dependent manner (0.5-10 microM) with an IC50 of 651.9 nM. In vivo 500 microg/kg i.p. dose of SB366791 significantly inhibited capsaicin-induced hypothermia, wiping movements and vasodilatation in the knee joint, while 2 mg/kg capsazepine was ineffective, its effect lasted for 1h. However, neither antagonist was able to inhibit capsaicin-evoked hypothermia in Balb/c mice. Based on these data SB366791 is a more selective and in vivo also a more potent TRPV1 receptor antagonist than capsazepine in the rat therefore, it may promote the assessment of the therapeutic utility of TRPV1 channel blockers.

Topics: Analgesics; Anilides; Animals; Capsaicin; Cells, Cultured; Cinnamates; Dose-Response Relationship, Drug; Drug Interactions; Hypothermia; Ion Channels; Male; Mice; Mice, Inbred BALB C; Neurons, Afferent; Nociceptors; Pain; Peripheral Nervous System; Rats; Rats, Wistar; Sensory Receptor Cells; Substance P; Trigeminal Ganglion; TRPV Cation Channels

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