NeuropharmacologyEffects of the transient receptor potential vanilloid 1 antagonist A-425619 on body temperature and thermoregulation in the rat
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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Cited by (25)
Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis
2020, Pharmacology and TherapeuticsCitation Excerpt :For example, AMG0347 and AMG 517 increase Tb in both rats and mice (Garami et al., 2010; Steiner et al., 2007), whereas capsazepine (CPZ) increases Tb in guinea pigs but has no thermal effect in rats (Garami et al., 2010). Intriguingly, some TRPV1 antagonists (e.g., A-1165901, A-425619, AMG7905, and AMG8562) cause hypothermia instead of hyperthermia (Garami, Pakai, et al., 2018; Lehto et al., 2008; Mills et al., 2008). And yet other compounds appear to affect Tb regulation in a species-specific fashion, e.g., JYL1421 was shown to cause hyperthermia in dogs and cynomolgus monkeys [Fig. 2D and E; also see Gavva, Bannon, Surapaneni et al. (2007)] but hypothermia in rats [Fig. 3D; also see Garami et al. (2010)].
The effects of juvenile capsaicin desensitization in rats: Behavioral impairments
2014, Physiology and BehaviorCitation Excerpt :Plenty of studies are available on the changes of thermoregulation after neonatal or adult capsaicin desensitization in restrained animals — with inconsistent results [14,27,51,55]. Two studies in adult desensitized mice or rats with telemetry showed that capsaicin desensitization significantly increases the core temperature and results in a marked deficit in heat tolerance [43,54]. We also found more pronounced changes in the warm than in the cold condition.
Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease
2011, BloodCitation Excerpt :The 100 μmol/kg dose of A-425619 was selected because it had the greatest antinociceptive effect in the complete Freund's adjuvant model of peripheral inflammation in rats and did not induce any effect on motor activity, general CNS function, or spontaneous exploratory activity.11 We did not measure changes in body temperature after administration of A-425619; however, transient hyperthermia followed by hypothermia has been observed in rats administered this compound.12 Recent evidence indicates that the hyperthermia-inducing effects of TRPV1 antagonists including A-425619 is due to their ability to block the proton-binding site on TRPV1.13
Characterization of 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]- (4-trifluoromethyl-phenyl)-amine (JNJ-39729209) as a novel TRPV1 antagonist
2011, European Journal of PharmacologyCitation Excerpt :In preclinical studies it was noted that the temperature elevation caused by ABT-102 was modest (0.6 °C) and short lived (Honore et al., 2009). Similar modest effects were seen with A-425619 (1 °C; Mills et al., 2008), AMG-8163 (0.5–0.8 °C; Gavva et al., 2007a) and JNJ-17203212 (0.8 °C; Swanson et al., 2005) and increases in body temperature ranging from 0.4 °C to 1.4 °C were noted with a variety of TRPV1 antagonists in a study by Gavva et al. (2007b). More recently researchers at Amgen have described two TRPV1 antagonists (JYL1421 and AMG-8562) that had no effect on body temperature in rats despite evidence of target engagement (Lehto et al., 2008).
The paradoxical role of the transient receptor potential vanilloid 1 receptor in inflammation
2010, Pharmacology and TherapeuticsTRPV1 antagonists: the challenges for therapeutic targeting
2009, Trends in Molecular MedicineCitation Excerpt :One reported antagonist that blocks pain behavior without affecting body temperature is V377 by PharmEste [90]. Another compound with unique action on body temperature regulation is A-425619, which paradoxically evokes a hypothermic effect after a transient initial febrile reaction [91]. A potential problem with AMG 8562 is its unexpected ability to potentiate proton-induced Ca2+ influx in TRPV1-expressing cells [89].