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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Cannabidiol is a negative allosteric modulator of the cannabinoid CB<sub>1</sub> receptor</title><author><name sortKey="Laprairie, R B" sort="Laprairie, R B" uniqKey="Laprairie R" first="R B" last="Laprairie">R B Laprairie</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Bagher, A M" sort="Bagher, A M" uniqKey="Bagher A" first="A M" last="Bagher">A M Bagher</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Kelly, M E M" sort="Kelly, M E M" uniqKey="Kelly M" first="M E M" last="Kelly">M E M. Kelly</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph13250-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Denovan Right, E M" sort="Denovan Right, E M" uniqKey="Denovan Right E" first="E M" last="Denovan-Wright">E M Denovan-Wright</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26218440</idno><idno type="pmc">4621983</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621983</idno><idno type="RBID">PMC:4621983</idno><idno type="doi">10.1111/bph.13250</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000027</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000027</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cannabidiol is a negative allosteric modulator of the cannabinoid CB<sub>1</sub> receptor</title><author><name sortKey="Laprairie, R B" sort="Laprairie, R B" uniqKey="Laprairie R" first="R B" last="Laprairie">R B Laprairie</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Bagher, A M" sort="Bagher, A M" uniqKey="Bagher A" first="A M" last="Bagher">A M Bagher</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation></author><author><name sortKey="Kelly, M E M" sort="Kelly, M E M" uniqKey="Kelly M" first="M E M" last="Kelly">M E M. Kelly</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation><affiliation><nlm:aff id="bph13250-aff-0002"></nlm:aff></affiliation></author><author><name sortKey="Denovan Right, E M" sort="Denovan Right, E M" uniqKey="Denovan Right E" first="E M" last="Denovan-Wright">E M Denovan-Wright</name><affiliation><nlm:aff id="bph13250-aff-0001"></nlm:aff></affiliation></author></analytic><series><title level="j">British Journal of Pharmacology</title><idno type="ISSN">0007-1188</idno><idno type="eISSN">1476-5381</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="bph13250-sec-0001"><title>Background and Purpose</title><p>Cannabidiol has been reported to act as an antagonist at cannabinoid CB<sub>1</sub> receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB<sub>1</sub> receptors.</p></sec><sec id="bph13250-sec-0002"><title>Experimental Approach</title><p>Internalization of CB<sub>1</sub> receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB<sub>1</sub> receptors and in the ST<italic>Hdh</italic><sup>Q7/Q7</sup> cell model of striatal neurons endogenously expressing CB<sub>1</sub> receptors. Cells were treated with 2‐arachidonylglycerol or Δ<sup>9</sup>‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.</p></sec><sec id="bph13250-sec-0003"><title>Key Results</title><p>Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ<sup>9</sup>‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (ST<italic>Hdh</italic><sup>Q7/Q7</sup>) expressing CB<sub>1</sub> receptors. By reducing arrestin2 recruitment to CB<sub>1</sub> receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB<sub>1</sub> receptor.</p></sec><sec id="bph13250-sec-0004"><title>Conclusions and Implications</title><p>Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB<sub>1</sub> receptors. Allosteric modulation, in conjunction with effects not mediated by CB<sub>1</sub> receptors, may explain the <italic>in vivo</italic> effects of cannabidiol. Allosteric modulators of CB<sub>1</sub> receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Br J Pharmacol</journal-id><journal-id journal-id-type="iso-abbrev">Br. J. Pharmacol</journal-id><journal-id journal-id-type="doi">10.1111/(ISSN)1476-5381</journal-id><journal-id journal-id-type="publisher-id">BPH</journal-id><journal-title-group><journal-title>British Journal of Pharmacology</journal-title></journal-title-group><issn pub-type="ppub">0007-1188</issn><issn pub-type="epub">1476-5381</issn><publisher><publisher-name>John Wiley and Sons Inc.</publisher-name><publisher-loc>Hoboken</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26218440</article-id><article-id pub-id-type="pmc">4621983</article-id><article-id pub-id-type="doi">10.1111/bph.13250</article-id><article-id pub-id-type="publisher-id">BPH13250</article-id><article-id pub-id-type="other">2015-BJP-0184-RP.R1</article-id><article-categories><subj-group subj-group-type="overline"><subject>Research Paper</subject></subj-group><subj-group subj-group-type="heading"><subject>Research Papers</subject></subj-group></article-categories><title-group><article-title>Cannabidiol is a negative allosteric modulator of the cannabinoid CB<sub>1</sub> receptor</article-title><alt-title alt-title-type="right-running-head">Negative allosteric modulation of CB<sub>1</sub> by cannabidiol</alt-title><alt-title alt-title-type="left-running-head">R B Laprairie et al.</alt-title></title-group><contrib-group><contrib id="bph13250-cr-0001" contrib-type="author"><name><surname>Laprairie</surname><given-names>R B</given-names></name><xref ref-type="aff" rid="bph13250-aff-0001"><sup>1</sup></xref></contrib><contrib id="bph13250-cr-0002" contrib-type="author"><name><surname>Bagher</surname><given-names>A M</given-names></name><xref ref-type="aff" rid="bph13250-aff-0001"><sup>1</sup></xref></contrib><contrib id="bph13250-cr-0003" contrib-type="author"><name><surname>Kelly</surname><given-names>M E M</given-names></name><xref ref-type="aff" rid="bph13250-aff-0001"><sup>1</sup></xref><xref ref-type="aff" rid="bph13250-aff-0002"><sup>2</sup></xref></contrib><contrib id="bph13250-cr-0004" contrib-type="author" corresp="yes"><name><surname>Denovan‐Wright</surname><given-names>E M</given-names></name><xref ref-type="aff" rid="bph13250-aff-0001"><sup>1</sup></xref></contrib></contrib-group><aff id="bph13250-aff-0001"><label><sup>1</sup></label><named-content content-type="organisation-division">Departments of Pharmacology</named-content><institution>Dalhousie University</institution><named-content content-type="city">Halifax</named-content><named-content content-type="country-part">NS</named-content><country country="CA">Canada</country></aff><aff id="bph13250-aff-0002"><label><sup>2</sup></label><named-content content-type="organisation-division">Opthamology and Visual Sciences</named-content><institution>Dalhousie University</institution><named-content content-type="city">Halifax</named-content><named-content content-type="country-part">NS</named-content><country country="CA">Canada</country></aff><author-notes><corresp id="correspondenceTo"><label>*</label>Correspondence<break></break>Eileen M Denovan‐Wright, PhD, Department of Pharmacology, Dalhousie University, Rm 6E 5850 College St, Halifax, NS, B3H 4R2, Canada. E‐mail: <email>emdenova@dal.ca</email><break></break></corresp></author-notes><pub-date pub-type="epub"><day>13</day><month>10</month><year>2015</year></pub-date><pub-date pub-type="ppub"><month>10</month><year>2015</year></pub-date><volume>172</volume><issue>20</issue><issue-id pub-id-type="doi">10.1111/bph.2015.172.issue-20</issue-id><fpage>4790</fpage><lpage>4805</lpage><history><date date-type="received"><day>13</day><month>2</month><year>2015</year></date><date date-type="rev-recd"><day>04</day><month>6</month><year>2015</year></date><date date-type="accepted"><day>08</day><month>7</month><year>2015</year></date></history><permissions><pmc-comment> Copyright © 2015 The British Pharmacological Society </pmc-comment>
<copyright-statement content-type="article-copyright">© 2015 The British Pharmacological Society</copyright-statement></permissions><self-uri content-type="pdf" xlink:type="simple" xlink:href="file:BPH-172-4790.pdf"></self-uri><abstract abstract-type="main"><sec id="bph13250-sec-0001"><title>Background and Purpose</title><p>Cannabidiol has been reported to act as an antagonist at cannabinoid CB<sub>1</sub> receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB<sub>1</sub> receptors.</p></sec><sec id="bph13250-sec-0002"><title>Experimental Approach</title><p>Internalization of CB<sub>1</sub> receptors, arrestin2 recruitment, and PLCβ3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB<sub>1</sub> receptors and in the ST<italic>Hdh</italic><sup>Q7/Q7</sup> cell model of striatal neurons endogenously expressing CB<sub>1</sub> receptors. Cells were treated with 2‐arachidonylglycerol or Δ<sup>9</sup>‐tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol.</p></sec><sec id="bph13250-sec-0003"><title>Key Results</title><p>Cannabidiol reduced the efficacy and potency of 2‐arachidonylglycerol and Δ<sup>9</sup>‐tetrahydrocannabinol on PLCβ3‐ and ERK1/2‐dependent signalling in cells heterologously (HEK 293A) or endogenously (ST<italic>Hdh</italic><sup>Q7/Q7</sup>) expressing CB<sub>1</sub> receptors. By reducing arrestin2 recruitment to CB<sub>1</sub> receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB<sub>1</sub> receptor.</p></sec><sec id="bph13250-sec-0004"><title>Conclusions and Implications</title><p>Cannabidiol behaved as a non‐competitive negative allosteric modulator of CB<sub>1</sub> receptors. Allosteric modulation, in conjunction with effects not mediated by CB<sub>1</sub> receptors, may explain the <italic>in vivo</italic> effects of cannabidiol. Allosteric modulators of CB<sub>1</sub> receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.</p></sec></abstract><counts><page-count count="16"></page-count></counts><custom-meta-group><custom-meta><meta-name>source-schema-version-number</meta-name><meta-value>2.0</meta-value></custom-meta><custom-meta><meta-name>component-id</meta-name><meta-value>bph13250</meta-value></custom-meta><custom-meta><meta-name>cover-date</meta-name><meta-value>October 2015</meta-value></custom-meta><custom-meta><meta-name>details-of-publishers-convertor</meta-name><meta-value>Converter:WILEY_ML3GV2_TO_NLMPMC version:4.6.9 mode:remove_FC converted:04.11.2015</meta-value></custom-meta></custom-meta-group></article-meta><notes><p content-type="self-citation"><mixed-citation publication-type="journal" id="bph13250-cit-0000"><string-name><surname>Laprairie</surname>, <given-names>R. B.</given-names></string-name>, <string-name><surname>Bagher</surname>, <given-names>A. M.</given-names></string-name>, <string-name><surname>Kelly</surname>, <given-names>M. E. M.</given-names></string-name>, and <string-name><surname>Denovan‐Wright</surname>, <given-names>E. M.</given-names></string-name> (<year>2015</year>) <article-title>Cannabidiol is a negative allosteric modulator of the cannabinoid CB<sub>1</sub> receptor</article-title>. <source>British Journal of Pharmacology</source>, <volume>172</volume>: <fpage>4790</fpage>–<lpage>4805</lpage>. doi: <ext-link ext-link-type="doi" xlink:href="10.1111/bph.13250">10.1111/bph.13250</ext-link>.<pub-id pub-id-type="pmid">26218440</pub-id></mixed-citation></p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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