Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature

Regina M. Reilly, Heath A. McDonald, Pamela S. Puttfarcken, Shailen K. Joshi, La Geisha Lewis, Madhavi Pai, Pamela H. Franklin, Jason A. Segreti, Torben R. Neelands, Ping Han, Jun Chen, Patrick W. Mantyh, Joseph R. Ghilardi, Teresa M. Turner, Eric A. Voight, Jerome F. Daanen, Robert G. Schmidt, Arthur Gomtsyan, Michael E. Kort, Connie R. FaltynekPhilip R. Kym

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


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 generelated 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.

Original languageEnglish (US)
Pages (from-to)416-428
Number of pages13
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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