Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 May 9:8:36.
doi: 10.1186/1744-8069-8-36.

Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation

Narender R Gavva  1 , Carl Davis, Sonya G Lehto, Sara Rao, Weiya Wang, Dawn X D Zhu
Affiliations

Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation

Narender R Gavva et al. Mol Pain. .

Abstract

Background: Transient receptor potential cation channel subfamily M member 8 (TRPM8) is activated by cold temperature in vitro and has been demonstrated to act as a 'cold temperature sensor' in vivo. Although it is known that agonists of this 'cold temperature sensor', such as menthol and icilin, cause a transient increase in body temperature (Tb), it is not known if TRPM8 plays a role in Tb regulation. Since TRPM8 has been considered as a potential target for chronic pain therapeutics, we have investigated the role of TRPM8 in Tb regulation.

Results: We characterized five chemically distinct compounds (AMG0635, AMG2850, AMG8788, AMG9678, and Compound 496) as potent and selective antagonists of TRPM8 and tested their effects on Tb in rats and mice implanted with radiotelemetry probes. All five antagonists used in the study caused a transient decrease in Tb (maximum decrease of 0.98°C). Since thermoregulation is a homeostatic process that maintains Tb about 37°C, we further evaluated whether repeated administration of an antagonist attenuated the decrease in Tb. Indeed, repeated daily administration of AMG9678 for four consecutive days showed a reduction in the magnitude of the Tb decrease Day 2 onwards.

Conclusions: The data reported here demonstrate that TRPM8 channels play a role in Tb regulation. Further, a reduction of magnitude in Tb decrease after repeated dosing of an antagonist suggests that TRPM8's role in Tb maintenance may not pose an issue for developing TRPM8 antagonists as therapeutics.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Characterization of five distinct compounds as TRPM8 antagonists. A) chemical structures of antagonists used in the study. B) Concentration dependent effects of antagonists on menthol-induced intracellular calcium increase in CHO cells stably expressing rat TRPM8. C) Concentration dependent effects of antagonists on cold (10°C)-induced intracellular calcium increase in CHO cells stably expressing rat TRPM8. Each data point in the graph are average ± S.D. of an experiment conducted in triplicate.
Figure 2
Figure 2
Effects of TRPM8 antagonists on body temperature (Tb) in rats or mice. Data are presented as mean ± S.E.M. of temperature collected for every 10 min. Statistical significance is relative to the vehicle (one tail unpaired t-test). Baseline Tb was collected for 20–30 min before compound administration (p.o.) at time 0 and post dosing every 10 min for 120 min (A) or 240 min ( B &C). The stress-induced transient increase in Tb seen right after antagonist administration is indicated by vertical dotted lines. A) AMG8788 dosed at 30 mg/kg significantly decreased rat Tb by 0.53°C at 40 min (t10 = 2.55; p < 0.05). B) AMG2850 dosed at 100 mg/kg significantly decreased rat Tb by 0.98°C at 140 min (t10 = 4.38; p < 0.001). C) AMG2850 dosed at 100 mg/kg significantly decreased mouse Tb by 0.73°C at 100 min (t17 = 2.99; p < 0.001). D) TRPM8 antagonist AMG9678 induced decrease in body temperature is transient in nature. Statistical significance is relative to vehicle (one way ANOVA followed by Dunnett’s Multiple Comparison Test). Baseline Tb was collected at 30 min before compound administration (p.o.) at time 0 and post dosing every 1 h for 24 h. At 100 mg/kg, AMG9678 significantly decreased Tb by 0.83°C at 1 hour (F3,22 = 6.46, p < 0.01), whereas at the same time, the maximum decrease of Tb was 0.7 and 0.72 0 C at 30 mg/kg and 10 mg/kg, respectively.
Figure 3
Figure 3
AMG9678-induced decrease in Tbpartially attenuates after repeat dosing in rats. AMG9678 was administered (p.o.) each day at 9:00 am for 4 days as indicated by an arrow. Tb data was collected every hour for 80 h and are presented as mean ± S.E.M. A) AMG9678 at 30 mg/kg produced a significant decrease of Tb by 0.62°C at 5 h (t14 = 4.27, p < 0.001), 0.47°C at 26 h ( t14 = 4.95, p < 0.001), 0.51°C at 52 h ( t14 = 5.01, p < 0.0001), and 0.38°C at 75 h ( t14 = 2.68, p < 0.01), respectively. The decrease in Tb lasted for 7 h post 1st dosing, 5 h post 2nd dosing, 5 h post 3rd dosing and 6 h post 4th dosing, respectively. B. AMG9678-induced decrease in Tb reduced on day 2–4 compared to day 1. Bars represent mean ± S.E.M. of ΔT of average 1–7 h post dosing on days 1–4.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Hensel H, Zotterman Y. Action potentials of cold fibres and intracutaneous temperature gradient. J Neurophysiol. 1951;14(5):377–85. - PubMed
    1. Hensel H, Zotterman Y. The response of the cold receptors to constant cooling. Acta Physiol Scand. 1951;22(2–3):96–105. - PubMed
    1. Hensel H, Zotterman Y. The effect of menthol on the thermoreceptors. Acta Physiol Scand. 1951;24(1):27–34. doi: 10.1111/j.1748-1716.1951.tb00824.x. - DOI - PubMed
    1. Suto K, Gotoh H. Calcium signaling in cold cells studied in cultured dorsal root ganglion neurons. Neuroscience. 1999;92(3):1131–5. doi: 10.1016/S0306-4522(99)00063-9. - DOI - PubMed
    1. Reid G, Flonta ML. Ion channels activated by cold and menthol in cultured rat dorsal root ganglion neurones. Neurosci Lett. 2002;324(2):164–8. doi: 10.1016/S0304-3940(02)00181-7. - DOI - PubMed

LinkOut - more resources