Effects of the transient receptor potential vanilloid 1 antagonist A-425619 on body temperature and thermoregulation in the rat
| Autor: | R. Jaffe, E. Zininberg, M. McMackin, D. Slee, Charles D. Mills, K. Gogas, M. Bradbury, J. Yu |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Hyperthermia medicine.medical_specialty Time Factors Fever Hypothalamus TRPV1 Administration Oral TRPV Cation Channels Hypothermia Motor Activity Drug Administration Schedule Body Temperature Rats Sprague-Dawley Oral administration Internal medicine medicine Animals Urea Circadian rhythm Chemistry General Neuroscience Antagonist Thermoregulation Isoquinolines medicine.disease Circadian Rhythm Rats Endocrinology Systemic administration Capsaicin medicine.symptom Body Temperature Regulation |
| Zdroj: | Neuroscience. 156:165-174 |
| ISSN: | 0306-4522 |
| Popis: | 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 (T(b)) 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 T(b) 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 T(b) similar to a single administration. A-425619 had no effect on T(b) 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 T(b) 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. |
| Databáze: | OpenAIRE |
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