Elsevier

Neuroscience

Volume 156, Issue 1, 22 September 2008, Pages 165-174
Neuroscience

Neuropharmacology
Effects of the transient receptor potential vanilloid 1 antagonist A-425619 on body temperature and thermoregulation in the rat

https://doi.org/10.1016/j.neuroscience.2008.06.069Get rights and content

Abstract

Transient receptor potential vanilloid 1 (TRPV1) receptor antagonists have gained much attention for their potential to treat inflammatory and neuropathic pain. However, systemic administration of TRPV1 antagonists induces a period of hyperthermia, a potential liability for small molecule development. Here we characterize the effects of the TRPV1 antagonist A-425619 on body temperature (Tb) in the rat when administered: (1) alone at different times of the circadian cycle, (2) as repeated hourly or daily treatment, (3) as pre-treatment to prevent capsaicin-induced hypothermia, (4) to capsaicin-desensitized animals, and (5) prior to a heat challenge. Changes in Tb were compared with compound exposure data, locomotor activity, and time course of efficacy in inflammatory pain models. Without affecting locomotor activity, oral administration of A-425619 induced a transient period of hyperthermia that was followed by a period of hypothermia, a profile unique among reported TRPV1 antagonists. Repeated hourly administration of A-425619 produced an increase in Tb similar to a single administration. A-425619 had no effect on Tb when administered to capsaicin-desensitized rats. The duration of A-425619-induced hyperthermia, but not hypothermia, was dependent on the time of the circadian cycle when administered. Pre-treatment with A-425619 attenuated capsaicin-induced hypothermia and did not potentiate Tb or alter thermoregulatory behavioral responses during a heat challenge. These results indicate that A-425619-induced hyperthermia is transient, circadian-dependent, not related to exposure levels, locomotor activity, or time course of analgesic action, and does not affect the ability to thermoregulate during a heat challenge.

Section snippets

Experimental animals, capsaicin and complete Freud's adjuvant (CFA) injections

Adult male Sprague–Dawley rats, 190–210 g, were obtained from Harlan (Indianapolis, IN, USA) and housed with a 12-h light/dark cycle. All procedures were approved by the Institutional Animal Care and Use Committee and in accordance with IASP guidelines. Efforts were taken to minimize the number of animals used and the extent of their suffering. All behavioral experiments were conducted in a randomized, blinded fashion. For s.c. capsaicin injection, capsaicin (Sigma-Aldrich, St. Louis, MO, USA)

A-425619 effects on Tb

Recently developed TRPV1 antagonists, such as AMG 517 (Gavva et al., 2007a) and AMG0347 (Steiner et al., 2007), induce changes in core Tb; therefore, we evaluated the effects of A-425619 on Tb when administered alone at the onset of the dark cycle (Fig. 1). A-425619 at 3.5 mg/kg produced a slight, statistically insignificant increase in Tb; whereas, 35 mg/kg induced a transient, significant increase in core Tb as determined by maximum change in Tb (P<0.01) and area under the curve (P<0.01) from

Discussion

When given systemically, capsaicin induces an immediate dose-dependent hypothermia followed by a period of hyperthermia (Jancso-Gabor et al 1970a, Szikszay et al 1982). Several TRPV1 antagonists produce hyperthermia that persists longer than 2 h, a response opposite to that of the initial hypothermia induced by capsaicin (Swanson et al 2005, Gavva et al 2007a, Gavva et al 2007b). Here we show that A-425619 also induces a period of hyperthermia; however, unlike previously reported TRPV1

Conclusion

Development of TRPV1 antagonists as therapeutic agents for inflammatory and neuropathic pain is hindered by increases in Tb associated with these compounds. We report that A-425619 has a Tb profile unique among TRPV1 antagonists, displaying both a hyper- and hypothermic period. The A-425619-induced increase in Tb is transient, requires TRPV1 expression, is circadian dependent, does not attenuate with repeated administration, and does not reflect a loss of thermoregulatory ability. The increase

Acknowledgments

The authors wish to thank Jason Hill for technical assistance.

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