title: Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia.
abstract: Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.
authors.affiliation: Systemic Inflammation Laboratory, Trauma Research, St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
authors.forename: Andras
authors.initials: A
authors.lastname: Garami
authors.forename: Yury P
authors.initials: YP
authors.lastname: Shimansky
authors.forename: Eszter
authors.initials: E
authors.lastname: Pakai
authors.forename: Daniela L
authors.initials: DL
authors.lastname: Oliveira
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Andrej A
authors.initials: AA
authors.lastname: Romanovsky
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000037:antagonists & inhibitors; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005334:Fever / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D006168:Guinea Pigs; D006358:Hot Temperature / Q000009:adverse effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009480:Neuropharmacology / Q000379:methods; D061766:Proton Therapy; D051381:Rats; D017208:Rats, Wistar; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D018689:Sensory System Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin