Pharmacology of Modality-Specific Transient Receptor Potential Vanilloid-1 Antagonists That Do Not Alter Body Temperature
Authors:
- Heath A. McDonaldHMHeath A. McDonald
- Pamela S. PuttfarckenPPPamela S. Puttfarcken
- Shailen K. JoshiSJShailen K. Joshi
- LaGeisha LewisLLLaGeisha Lewis
- Madhavi PaiMPMadhavi Pai
- Pamela H. FranklinPFPamela H. Franklin
- Jason A. SegretiJSJason A. Segreti
- Torben R. NeelandsTNTorben R. Neelands
- Ping HanPHPing Han
- Jun ChenJCJun Chen
- Patrick W. MantyhPMPatrick W. Mantyh
- 1 August 2012
- journal article
- Published by Elsevier in The Journal of Pharmacology and Experimental Therapeutics
- Vol. 342 (2) , 416-428
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 Ca2+ 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.Keywords
This publication has 43 references indexed in Scilit:
- Thermoregulatory Phenotype of theTrpv1Knockout Mouse: Thermoeffector Dysbalance with HyperkinesisJournal of Neuroscience, 2011
- Transient receptor potential channels and vascular functionClinical Science, 2010
- Treatment of painful bone metastasesNature Reviews Clinical Oncology, 2010
- Contributions of Different Modes of TRPV1 Activation to TRPV1 Antagonist-Induced HyperthermiaJournal of Neuroscience, 2010
- Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1Trends in Pharmacological Sciences, 2008
- (R)-(5-tert-Butyl-2,3-dihydro-1 H-inden-1-yl)-3-(1 H-indazol-4-yl)-urea (ABT-102) Blocks Polymodal Activation of Transient Receptor Potential Vanilloid 1 Receptors in Vitro and Heat-Evoked Firing of Spinal Dorsal Horn Neurons in VivoThe Journal of Pharmacology and Experimental Therapeutics, 2008
- Nonthermal Activation of Transient Receptor Potential Vanilloid-1 Channels in Abdominal Viscera Tonically Inhibits Autonomic Cold-Defense EffectorsJournal of Neuroscience, 2007
- Arthritis and pain. Future targets to control osteoarthritis painArthritis Research & Therapy, 2007
- Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spinesProceedings of the National Academy of Sciences, 2006
- Proton Activation Does Not Alter Antagonist Interaction with the Capsaicin-Binding Pocket of TRPV1Molecular Pharmacology, 2005