Effects of the transient receptor potential vanilloid 1 antagonist A-425619 on body temperature and thermoregulation in the rat.
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.
Mills
C
C
Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA. cmills@neurocrine.com
McMackin
M
M
Jaffe
R
R
Yu
J
J
Zininberg
E
E
Slee
D
D
Gogas
K
K
Bradbury
M
M
D000284:Administration, Oral; D000818:Animals; D001831:Body Temperature / Q000187:drug effects* / Q000502:physiology; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000502:physiology; D002211:Capsaicin / Q000037:antagonists & inhibitors; D002940:Circadian Rhythm / Q000187:drug effects* / Q000502:physiology; D004334:Drug Administration Schedule; D005334:Fever / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
C503120:1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea; D007546:Isoquinolines; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014508:Urea; D002211:Capsaicin