Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene

Abstract

Background

TRPA1 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 TRPA1 channel.

Methods

We examine the effects of limonene on sensory neurons from wild-type, TRPV1- and TRPA1-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 Ca²⁺ concentration ([Ca²⁺]_i), which was inhibited by selective inhibitors of TRPA1 but not TRPV1. Limonene-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. Limonene failed to stimulate sensory neurons from the TRPA1 (−/−) mouse. Heterologously expressed mouse TRPA1 was activated by limonene. Intraplantar injection of limonene elicited acute pain, which was significantly less in TRPA1 (−/−) mice. Systemic administration of limonene reduced nociceptive behaviours evoked by H₂O₂. In both heterologously and endogenously expressed TRPA1, a low concentration of limonene significantly inhibited H₂O₂-induced TRPA1 activation. TRPA1 activation by limonene was abolished in H₂O₂-insensitive cysteine-mutated channels.

Conclusions

Topically applied limonene stimulates TRPA1, 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 TRPA1 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 TRPA1 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 TRPA1 activation.

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