{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:32:04Z","timestamp":1790620324772,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T00:00:00Z","timestamp":1459382400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 is a Ca\u2010permeable 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\n                      <jats:styled-content style=\"fixed-case\">TRP<\/jats:styled-content>\n                      channel activity. Here, we report that limonene, being contained in citrus fruits and mushrooms, shows a unique bimodal action on\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 channel.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We examine the effects of limonene on sensory neurons from wild\u2010type,\n                      <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n                      1\u2010 and\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1\u2010gene\u2010deficient mice and on heterologously expressed channels\n                      <jats:italic>in\u00a0vitro<\/jats:italic>\n                      . 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\n                      <jats:italic>in\u00a0vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In wild\u2010type mouse sensory neurons, limonene increased the intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      concentration ([Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      ), which was inhibited by selective inhibitors of\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 but not\n                      <jats:styled-content style=\"fixed-case\">TRPV<\/jats:styled-content>\n                      1. Limonene\u2010responsive neurons highly corresponded to\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 agonist\u2010sensitive ones. Limonene failed to stimulate sensory neurons from the\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 (\u2212\/\u2212) mouse. Heterologously expressed mouse\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 was activated by limonene. Intraplantar injection of limonene elicited acute pain, which was significantly less in\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 (\u2212\/\u2212) mice. Systemic administration of limonene reduced nociceptive behaviours evoked by H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      . In both heterologously and endogenously expressed\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1, a low concentration of limonene significantly inhibited H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      \u2010induced\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 activation.\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 activation by limonene was abolished in H\n                      <jats:sub>2<\/jats:sub>\n                      O\n                      <jats:sub>2<\/jats:sub>\n                      \u2010insensitive cysteine\u2010mutated channels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Topically applied limonene stimulates\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      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\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 channels.\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:bold>What does this study add:<\/jats:bold>\n                      Limonene, a monoterpene in essential oils of various plants, has been known for its antitumor and anti\u2010inflammatory properties. However, molecular basis of their actions has not been identified. This study shows that limonene activates nociceptive\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      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\u2010induced\n                      <jats:styled-content style=\"fixed-case\">TRPA<\/jats:styled-content>\n                      1 activation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ejp.840","type":"journal-article","created":{"date-parts":[[2016,3,31]],"date-time":"2016-03-31T18:24:35Z","timestamp":1459448675000},"page":"1155-1165","source":"Crossref","is-referenced-by-count":53,"title":["Involvement of transient receptor potential A1 channel in algesic and analgesic actions of the organic compound limonene"],"prefix":"10.1002","volume":"20","author":[{"given":"T.","family":"Kaimoto","sequence":"first","affiliation":[{"name":"Department of Veterinary Pharmacology Faculty of Agriculture Tottori University Tottori 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