Desensitization of transient receptor potential ankyrin 1 (TRPA1) by the TRP vanilloid 1-selective cannabinoid arachidonoyl-2 chloroethanolamine

Nikita B. Ruparel, Amol M Patwardhan, Armen N. Akopian, Kenneth M. Hargreaves

Research output: Contribution to journalArticle

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Abstract

Recent studies on cannabinoid-induced analgesia implicate certain transient receptor potential (TRP) channels as a therapeutic target along with metabotropic cannabinoid receptors. Although TRP ankyrin 1 (TRPA1)-selective cannabinoids, such as (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1, 2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212), are effective at desensitizing TRPA1 and TRP vanilloid 1 (TRPV1), there is a gap in knowledge in understanding the opposite situation, namely whether TRPV1-selective cannabinoids desensitize TRPA1. We selected the TRPV1-specific synthetic cannabinoid, arachidonoyl-2 chloroethanolamine (ACEA), to study peripheral antihyperalgesic properties because ACEA is known to activate TRPV1. Hence, we used in vitro as well as in vivo assays to evaluate the following: 1) the effects of ACEA on the TRPA1-selective agonist, mustard oil (MO), for calcitonin generelated peptide (CGRP) release from rat hindpaw skin in vitro; 2) the effects of a peripherally selective dose of ACEA on MOinduced nocifensive behavior in vivo; and 3) the effects of five ACEA-insensitive TRPV1 mutations on ACEA-inhibition of MOevoked calcium accumulation using a Chinese hamster ovary cell expression system. Our results demonstrate that 1) ACEA significantly attenuated (∼40%) MO-evoked CGRP release from rat hindpaw skin, and this effect was not antagonized by the TRPV1 antagonist, capsazepine; 2) ACEA significantly inhibited (∼40%) MO-induced nocifensive behavior in wild-type mice but not in TRPV1 knockout mice; and 3) all TRPV1 mutations insensitive to ACEA lacked the ability to inhibit MO-evoked calcium accumulation in Chinese hamster ovary cells transfected with TRPV1 and TRPA1. Taken together, the results indicate that a TRPV1-selective cannabinoid, ACEA, inhibits MO-evoked responses via a TRPV1-dependent mechanism. This study strengthens the hypothesis that cannabinoids mediate their peripheral analgesic properties, at least in part, via the TRP channels.

Original languageEnglish (US)
Pages (from-to)117-123
Number of pages7
JournalMolecular Pharmacology
Volume80
Issue number1
DOIs
StatePublished - Jul 2011

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Ankyrins
Cannabinoids
Transient Receptor Potential Channels
Calcitonin
Cricetulus
Ovary
vanilloid receptor subtype 1
arachidonoyl-2 chloroethanolamine
trophoblastin
Psychologic Desensitization
Calcium
Cannabinoid Receptors
Skin
Peptides
Mutation
Aptitude
Knockout Mice
Analgesia
Analgesics
mustard oil

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Desensitization of transient receptor potential ankyrin 1 (TRPA1) by the TRP vanilloid 1-selective cannabinoid arachidonoyl-2 chloroethanolamine. / Ruparel, Nikita B.; Patwardhan, Amol M; Akopian, Armen N.; Hargreaves, Kenneth M.

In: Molecular Pharmacology, Vol. 80, No. 1, 07.2011, p. 117-123.

Research output: Contribution to journalArticle

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abstract = "Recent studies on cannabinoid-induced analgesia implicate certain transient receptor potential (TRP) channels as a therapeutic target along with metabotropic cannabinoid receptors. Although TRP ankyrin 1 (TRPA1)-selective cannabinoids, such as (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1, 2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55,212), are effective at desensitizing TRPA1 and TRP vanilloid 1 (TRPV1), there is a gap in knowledge in understanding the opposite situation, namely whether TRPV1-selective cannabinoids desensitize TRPA1. We selected the TRPV1-specific synthetic cannabinoid, arachidonoyl-2 chloroethanolamine (ACEA), to study peripheral antihyperalgesic properties because ACEA is known to activate TRPV1. Hence, we used in vitro as well as in vivo assays to evaluate the following: 1) the effects of ACEA on the TRPA1-selective agonist, mustard oil (MO), for calcitonin generelated peptide (CGRP) release from rat hindpaw skin in vitro; 2) the effects of a peripherally selective dose of ACEA on MOinduced nocifensive behavior in vivo; and 3) the effects of five ACEA-insensitive TRPV1 mutations on ACEA-inhibition of MOevoked calcium accumulation using a Chinese hamster ovary cell expression system. Our results demonstrate that 1) ACEA significantly attenuated (∼40{\%}) MO-evoked CGRP release from rat hindpaw skin, and this effect was not antagonized by the TRPV1 antagonist, capsazepine; 2) ACEA significantly inhibited (∼40{\%}) MO-induced nocifensive behavior in wild-type mice but not in TRPV1 knockout mice; and 3) all TRPV1 mutations insensitive to ACEA lacked the ability to inhibit MO-evoked calcium accumulation in Chinese hamster ovary cells transfected with TRPV1 and TRPA1. Taken together, the results indicate that a TRPV1-selective cannabinoid, ACEA, inhibits MO-evoked responses via a TRPV1-dependent mechanism. This study strengthens the hypothesis that cannabinoids mediate their peripheral analgesic properties, at least in part, via the TRP channels.",
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