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, LaGeisha 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 journalArticle

61 Citations (Scopus)

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 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
Volume342
Issue number2
DOIs
StatePublished - Aug 2012

Fingerprint

Body Temperature
Pharmacology
Capsaicin
Acids
Dopamine
vanilloid receptor subtype 1
Bone Neoplasms
Temperature
Aptitude
Electrophysiology
Arthralgia
Calcitonin
Knee Joint
Analgesia
Protons
Fever
Hot Temperature
Maintenance
Lipids
Pain

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature. / Reilly, Regina M.; McDonald, Heath A.; Puttfarcken, Pamela S.; Joshi, Shailen K.; Lewis, LaGeisha; Pai, Madhavi; Franklin, Pamela H.; Segreti, Jason A.; Neelands, Torben R.; Han, Ping; Chen, Jun; Mantyh, Patrick W; Ghilardi, Joseph R.; Turner, Teresa M.; Voight, Eric A.; Daanen, Jerome F.; Schmidt, Robert G.; Gomtsyan, Arthur; Kort, Michael E.; Faltynek, Connie R.; Kym, Philip R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 342, No. 2, 08.2012, p. 416-428.

Research output: Contribution to journalArticle

Reilly, RM, McDonald, HA, Puttfarcken, PS, Joshi, SK, Lewis, L, Pai, M, Franklin, PH, Segreti, JA, Neelands, TR, Han, P, Chen, J, Mantyh, PW, Ghilardi, JR, Turner, TM, Voight, EA, Daanen, JF, Schmidt, RG, Gomtsyan, A, Kort, ME, Faltynek, CR & Kym, PR 2012, 'Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature', Journal of Pharmacology and Experimental Therapeutics, vol. 342, no. 2, pp. 416-428. https://doi.org/10.1124/jpet.111.190314
Reilly, Regina M. ; McDonald, Heath A. ; Puttfarcken, Pamela S. ; Joshi, Shailen K. ; Lewis, LaGeisha ; Pai, Madhavi ; Franklin, Pamela H. ; Segreti, Jason A. ; Neelands, Torben R. ; Han, Ping ; Chen, Jun ; Mantyh, Patrick W ; Ghilardi, Joseph R. ; Turner, Teresa M. ; Voight, Eric A. ; Daanen, Jerome F. ; Schmidt, Robert G. ; Gomtsyan, Arthur ; Kort, Michael E. ; Faltynek, Connie R. ; Kym, Philip R. / Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 342, No. 2. pp. 416-428.
@article{fd49a573bef746d0bec685cf5d8fde3e,
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 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.",
author = "Reilly, {Regina M.} and McDonald, {Heath A.} and Puttfarcken, {Pamela S.} and Joshi, {Shailen K.} and LaGeisha Lewis and Madhavi Pai and Franklin, {Pamela H.} and Segreti, {Jason A.} and Neelands, {Torben R.} and Ping Han and Jun Chen and Mantyh, {Patrick W} and Ghilardi, {Joseph R.} and Turner, {Teresa M.} and Voight, {Eric A.} and Daanen, {Jerome F.} and Schmidt, {Robert G.} and Arthur Gomtsyan and Kort, {Michael E.} and Faltynek, {Connie R.} and Kym, {Philip R.}",
year = "2012",
month = "8",
doi = "10.1124/jpet.111.190314",
language = "English (US)",
volume = "342",
pages = "416--428",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature

AU - Reilly, Regina M.

AU - McDonald, Heath A.

AU - Puttfarcken, Pamela S.

AU - Joshi, Shailen K.

AU - Lewis, LaGeisha

AU - Pai, Madhavi

AU - Franklin, Pamela H.

AU - Segreti, Jason A.

AU - Neelands, Torben R.

AU - Han, Ping

AU - Chen, Jun

AU - Mantyh, Patrick W

AU - Ghilardi, Joseph R.

AU - Turner, Teresa M.

AU - Voight, Eric A.

AU - Daanen, Jerome F.

AU - Schmidt, Robert G.

AU - Gomtsyan, Arthur

AU - Kort, Michael E.

AU - Faltynek, Connie R.

AU - Kym, Philip R.

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84864147863&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864147863&partnerID=8YFLogxK

U2 - 10.1124/jpet.111.190314

DO - 10.1124/jpet.111.190314

M3 - Article

C2 - 22570364

AN - SCOPUS:84864147863

VL - 342

SP - 416

EP - 428

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 2

ER -