Elsevier

Life Sciences

Volume 82, Issues 23–24, 6 June 2008, Pages 1191-1195
Life Sciences

Capsaicin pretreatment attenuates LPS-induced hypothermia through TRPV1-independent mechanisms in chicken

https://doi.org/10.1016/j.lfs.2008.04.003Get rights and content

Abstract

It has been demonstrated that chicken TRPV1 (transient receptor potential vanilloid of subtype-1) is insensitive to capsaicin (CAP), and therefore, a chicken model is suitable to analyze the CAP-sensitive TRPV1-independent pathway. We elucidated here the possible involvement of the pathway in hypothermia induced by bacterial endotoxin (lipopolysaccharide, LPS) in chickens. Chicks were pretreated with CAP (10 mg/kg, iv) at 1, 2 and 3 days of age to desensitize them towards the CAP-sensitive pathway. An intravenous injection of LPS in 4-day-old chicks caused progressive hypothermia, ending with collapse and 78% mortality within 12 h after injection. The CAP pretreatment rescued the LPS-induced endotoxin shock and hypothermia in chicks. LPS-induced iNOS expression as well as NO production in liver and lung was suppressed by CAP pretreatment. CAP pretreatment also attenuated hypothermia due to exposure of chicks to cold ambient temperature. These findings suggest that a CAP-sensitive TRPV1-independent pathway may be involved in pathophysiological hypothermic reactions through the mediation of NO in chickens.

Introduction

Homeothermic animals are able to keep their body core temperature balanced within a very narrow range (within 1 °C) even when exposed to a wide range of ambient temperatures (Romanovsky, 2007). A change in this balance range is suggestive of a pathological condition. For instance, an injection of high doses of endotoxin lipopolysaccharide (LPS) induces septic shock manifested by hypothermia and hypotension (Romanovsky et al., 1996, Mailman et al., 1999). In mammals, LPS induces hypothermia by reducing metabolic heat production and by an induction of cold-seeking behavior, even though their body temperature is decreasing (Kluger, 1991, Steiner and Branco, 2002, Romanovsky et al., 2005, Rudaya et al., 2005, Almeida et al., 2006a, Almeida et al., 2006b). It is fundamentally accepted that LPS-induced hypothermia, as a sign of septic shock, is a brain mediated response and is triggered by release of cryogenic cytokines and free radicals like NO from LPS-processing organs, which is potentially lethal (Almeida et al., 2006a, Almeida et al., 2006b, Kluger, 1991, Romanovsky et al., 2005, Saia and Carnio, 2006).

It has been reported that pretreatment of capsaicin (CAP) blocks a part of LPS-induced fever in rats (Székely et al., 1997, Székely et al., 2000, Dogan et al., 2004, Pétervári et al., 2005). It is generally accepted that the action of CAP is mediated though the transient receptor potential vanilloid of subtype-1 (TRPV1) (Caterina et al., 1997). TRPV1 is involved in maintaining internal body temperature in mammals through autonomic thermoeffector mechanisms (skin vasculature and thermogenesis) (Steiner et al., 2007, Montell and Caterina, 2007). However, a TRPV1-independent pathway may be involved in febrile responses to LPS, since the effects of CAP are neither blocked by the selective competitive TRPV1 antagonist capsazepine nor mimicked by the specific TRPV1 agonist resiniferatoxin (Dogan et al., 2004). TRPV1 null mice may be valuable in proving the CAP-sensitive, TRPV1-independent pathway (Iida et al., 2005), although a deficiency of reactions to other stimuli mediated by TRPV1, such as heat or acid, should be always taken into consideration. Alternatively, a chicken model is suitable for analysis of the CAP-sensitive, TRPV1-independent pathway, because chicken TRPV1 is insensitive to CAP but possesses an equivalent responsiveness as mammalian TRPV1 to other stimuli (Julius and Basbaum, 2001, Jordt and Julius, 2002). In fact, we have recently demonstrated, by using the chicken model, that a CAP-sensitive, TRPV1-independent pathway mediates the fever induced by LPS (Mahmoud et al., 2007). A similar conclusion has been made by Dogan et al. (2004) based on their study in a mammalian species (rat).

In the present study, we used the chicken model to investigate involvement of a TRPV1-independent pathway in hypothermia induced by a high dose of LPS. Our findings show that a CAP-sensitive, TRPV1-independent pathway is involved in LPS-induced hypothermic shock in chicken. The involvement of this pathway in cold-induced hypothermia is also clarified.

Section snippets

Animals

Male, newly hatched white leghorn chicks, specific pathogen free, were brought from Goto Chick Company (Gifu, Japan) with a body weight range of 40 ± 7 g. Chicks were kept on a 12:12 h light–dark cycle in thermostatically controlled cages. To match the chicks' requirements, the temperature of the cage for the newly hatched chicks was set at 35 °C and then decreased 0.5 °C every day until day 4. All procedures were approved by the Local Committee for Ethics of Animal Experimentation, Care and Use

Survivability

In order to determine the LD50 of endotoxin LPS in chicks, 4-day-old chicks were injected intravenously with different doses of LPS (1, 5, 10, 20 mg/kg), and survivals were monitored every 3 h over the next 12 h. LPS increased lethality dose-dependently with a calculated LD50 at 12 h with 7.0 mg/kg. Therefore, we chose the dose of 10 mg/kg as an optimum to induce the experimental endotoxin shock. Fig. 1 shows that survivability of chicks at 12 h after LPS injection (10 mg/kg, iv) was about 20%.

Discussion

In a previous study (Mahmoud et al., 2007), we found that desensitization of the CAP-sensitive pathway abolishes the febrile response to LPS in chicken. Based on this observation, we have concluded that a CAP-sensitive, “TRPV1-independent” pathway would be related to LPS-induced fever, because TRPV1 in chickens does not react with CAP. Taking advantage of the chicken model, in the present study, we analyzed the involvements of the TRPV1-independent pathway in hypothermia induced by a relatively

Acknowledgments

The authors are grateful to Goto Chick Company, Gifu, Japan for kindly providing one-day male leghorn chicks. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

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These authors contributed equally to this work.

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