Effects of the capsaicin analogue resiniferatoxin on thermoregulation in anesthetized rats

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Abstract

(1) Administration of resiniferatoxin (RTX; 50 μg/kg, s.c.) induced triphasic metabolic responses with immediate facilitation followed by transitory inhibition and subsequent long-lasting facilitation in urethan-anesthetized rats. The temperature of skin increased immediately after the RTX injection, suggesting cutaneous vasodilation and heat loss. The colonic temperature decreased initially and then increased above the baseline level. (2) Pretreatment with ruthenium red, a putative vanilloid receptor (VN2) antagonist, attenuated the RTX-induced heat loss and inhibition of heat production. (3) Adrenal demedullation selectively attenuated the RTX-induced immediate thermogenesis, and the β-blocker propranolol prevented both phases of thermogenesis. Thus, the sympathetic nervous system and adrenaline contributed to the thermogenic responses.

Introduction

Resiniferatoxin (RTX), found in the plant genus Euphorbia, is an ultrapotent capsaicin analogue. RTX and capsaicin share a homovanillyl moiety as a structural motif essential for bioactivity and thus are called vanilloids. Systemic administration of RTX or capsaicin induces marked hypothermia in mammals (Szolcsányi, 1982; Hori, 1984; De Vries and Blumberg, 1989; Andrews and Bhandari, 1993; Woods et al., 1994). The vanilloid-induced hypothermia is a result of coordinated heat loss responses such as cutaneous vasodilation, sweating, and panting (Hori, 1984).

However, the effects of vanilloids on heat production vary among preparations. Capsaicin activated adrenaline-mediated heat production simultaneously with the heat loss responses in anesthetized rats (Kawada et al., 1986; Watanabe et al., 1988; Kobayashi et al., 1998; Osaka et al., 2000), whereas administration of RTX decreased heat production at an ambient temperature (Ta) of 20°C but had no effect at thermoneutrality (Ta=29°C) in awake rats (Woods et al., 1994). On the other hand, RTX and capsaicin stimulated O2 consumption (VO2), an index of heat production, in perfused rat hindlimb preparations through non-adrenergic mechanisms at low concentrations; whereas at high concentrations they caused triphasic VO2 responses with an initial transient facilitation followed by steady-state inhibition and transient facilitation after removal of the drug (Eldershaw et al., 1994; Colquhoun et al., 1995). Two different vanilloid receptors (VN1 and VN2) have been proposed based on pharmacological studies on isolated hindlimb preparations: VN1 stimulated VO2 and was antagonized by capsazepine, whereas VN2 inhibited VO2 and was antagonized by ruthenium red (Colquhoun et al., 1995; Griffiths et al., 1996). The aim of the present study was to characterize the effects of RTX on heat production and heat loss and to clarify the involvement of vanilloid receptors in these responses in anesthetized rats. For this purpose, we simultaneously recorded VO2, colonic temperature (Tc), and tail skin temperature (Ts). Then, we examined the effects of capsaicin desensitization, pretreatment with vanilloid antagonists ruthenium red and capsazepine, adrenal demedullation, and pretreatment with the β-blocker propranolol on the RTX-induced responses in the thermoregulatory system.

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Materials and methods

Male Wistar rats (Rattus norvegicus), weighing 250–300 g, were anesthetized with urethan (1.1 g/kg, i.p.) and placed on a heating pad to maintain their baseline body temperature at ∼36°C during the experiment. The care of animals and all surgical procedures followed institutional guidelines. Animals were killed by an overdose of anesthetic at the end of the experiment. RTX (95% purity, Sigma Chemical) was dissolved in saline containing 10% ethanol and 10% Tween 80 and injected at 50 μg/kg (s.c.)

Results

Administration of RTX elicited triphasic changes in VO2 in control rats (Fig. 1A, n=9). VO2 increased immediately after the RTX injection, reaching a peak of 12.9±0.5 ml/min/kg0.75 at 50–60 min, then decreased to a minimal value of 11.5±0.5 ml/min/kg0.75 at 100 min, and subsequently increased again, remaining elevated until at least 300 min. Tc decreased immediately after the RTX injection to a minimal value of 35.8±0.1°C at 20–55 min, and subsequently increased beyond the baseline level for 65–300 

Discussion

In the present study, we confirmed previous results showing that RTX induced a fall in Tc (De Vries and Blumberg, 1989; Andrews and Bhandari, 1993; Woods et al., 1994). This hypothermia was accompanied by an increase in Ts, suggesting cutaneous vasodilation and activation of heat loss. These RTX-induced changes in Tc and Ts were similar to those after capsaicin administration (Hori, 1984; Kobayashi et al., 1998; Osaka et al., 2000). However, RTX induced triphasic changes in VO2 with initial

Acknowledgments

This work was supported in part by the Japan Health Sciences Foundation.

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