title: Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.
abstract: The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.
authors.affiliation: Departments of Neuroscience Research and Integrative Pharmacology, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA.
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Puttfarcken
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.forename: LaGeisha
authors.initials: L
authors.lastname: Lewis
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Franklin
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.forename: Torben R
authors.initials: TR
authors.lastname: Neelands
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ghilardi
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Turner
authors.forename: Eric A
authors.initials: EA
authors.lastname: Voight
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002461:Cell Line, Transformed; D005334:Fever / Q000188:drug therapy / Q000503:physiopathology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011522:Protons; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000700:Analgesics; D011522:Protons; D011994:Recombinant Proteins; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D002118:Calcium