Premium
Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene
Author(s) -
Kaimoto T.,
Hatakeyama Y.,
Takahashi K.,
Imagawa T.,
Tominaga M.,
Ohta T.
Publication year - 2016
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.840
Subject(s) - transient receptor potential channel , chemistry , pharmacology , trpv , limonene , biochemistry , biophysics , trpv1 , receptor , biology , food science , essential oil
Background TRPA 1 is a Ca‐permeable nonselective cation channel expressed in sensory neurons and acts as a nocisensor. Recent reports show that some monoterpenes, a group of naturally occurring organic compounds, modulate TRP channel activity. Here, we report that limonene, being contained in citrus fruits and mushrooms, shows a unique bimodal action on TRPA 1 channel. Methods We examine the effects of limonene on sensory neurons from wild‐type, TRPV 1‐ and TRPA 1‐gene‐deficient mice and on heterologously expressed channels in vitro . Molecular determinants were identified with using mutated channels. Cellular excitability is monitored with ratiometric Ca imaging. Nociceptive and analgesic actions of limonene are also examined in vivo . Results In wild‐type mouse sensory neurons, limonene increased the intracellular Ca 2+ concentration ([Ca 2+ ] i ), which was inhibited by selective inhibitors of TRPA 1 but not TRPV 1. Limonene‐responsive neurons highly corresponded to TRPA 1 agonist‐sensitive ones. Limonene failed to stimulate sensory neurons from the TRPA 1 (−/−) mouse. Heterologously expressed mouse TRPA 1 was activated by limonene. Intraplantar injection of limonene elicited acute pain, which was significantly less in TRPA 1 (−/−) mice. Systemic administration of limonene reduced nociceptive behaviours evoked by H 2 O 2 . In both heterologously and endogenously expressed TRPA 1, a low concentration of limonene significantly inhibited H 2 O 2 ‐induced TRPA 1 activation. TRPA 1 activation by limonene was abolished in H 2 O 2 ‐insensitive cysteine‐mutated channels. Conclusions Topically applied limonene stimulates TRPA 1, resulting in elicitation of acute pain, but its systemic application inhibits nociception induced by oxidative stress. Because limonene is a safe compound, it may be utilized for pain control due to its inhibition of TRPA 1 channels. What does this study add: Limonene, a monoterpene in essential oils of various plants, has been known for its antitumor and anti‐inflammatory properties. However, molecular basis of their actions has not been identified. This study shows that limonene activates nociceptive TRPA 1 and elicits acute pain, when it is topically applied. In addition, systemic application of limonene exerts inhibitory effects on nociception induced by an oxidative stress‐induced TRPA 1 activation.