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Given recent findings of CB<jats:sub>2<\/jats:sub> and GPR55 receptors in the brain, we examined whether these receptors are also involved in cannabinoid action.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We compared \u0394<jats:sup>9<\/jats:sup>\u2010tetrahydrocannabinol (\u0394<jats:sup>9<\/jats:sup>\u2010THC)\u2010, WIN55212\u20102\u2010, or XLR11\u2010induced tetrad effects between wild\u2010type (WT) and each genotype of CB<jats:sub>1<\/jats:sub>\u2010, CB<jats:sub>2<\/jats:sub>\u2010 or GPR55\u2010knockout (KO) mice and then observed the effects of antagonists of these receptors on these tetrad effects in WT mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Systemic administration of \u0394<jats:sup>9<\/jats:sup>\u2010THC, WIN55212\u20102 or XLR11 produced dose\u2010dependent tetrad effects in WT mice. Genetic deletion or pharmacological blockade of CB<jats:sub>1<\/jats:sub> receptors abolished the tetrad effects produced by all three cannabinoids. Unexpectedly, genetic deletion of CB<jats:sub>2<\/jats:sub> receptor abolished analgesia and catalepsy produced by \u0394<jats:sup>9<\/jats:sup>\u2010THC or WIN55212\u20102, but not by XLR11. Microinjections of \u0394<jats:sup>9<\/jats:sup>\u2010THC into the lateral ventricles also produced tetrad effects in WT, but not in CB<jats:sub>1<\/jats:sub>\u2010KO mice. CB<jats:sub>2<\/jats:sub>\u2010KO mice displayed a reduction in intraventricular \u0394<jats:sup>9<\/jats:sup>\u2010THC\u2010induced analgesia and catalepsy. In contrast to CB<jats:sub>1<\/jats:sub> and CB<jats:sub>2<\/jats:sub> receptors, genetic deletion of GPR55 receptors caused enhanced responses to \u0394<jats:sup>9<\/jats:sup>\u2010THC or WIN55212\u20102. Antagonisim of CB<jats:sub>1<\/jats:sub>, CB<jats:sub>2<\/jats:sub> or GPR55 receptors produced alterations similar to those observed in each genotype mouse line.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These findings suggest that in addition to CB<jats:sub>1<\/jats:sub>, both CB<jats:sub>2<\/jats:sub> and GPR55 receptors are also involved in some pharmacological effects produced by cannabinoids. CB<jats:sub>1<\/jats:sub>\/CB<jats:sub>2<\/jats:sub>, in contrast to GPR55, receptors appears to play opposite roles in cannabinoid action.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14958","type":"journal-article","created":{"date-parts":[[2019,12,27]],"date-time":"2019-12-27T00:34:29Z","timestamp":1577406869000},"page":"1865-1880","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Different receptor mechanisms underlying phytocannabinoid\u2010 versus synthetic cannabinoid\u2010induced tetrad effects: Opposite roles of CB<sub>1<\/sub>\/CB<sub>2<\/sub> versus GPR55 receptors"],"prefix":"10.1111","volume":"177","author":[{"given":"Xiao\u2010Fei","family":"Wang","sequence":"first","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ewa","family":"Galaj","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Hua","family":"Bi","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cindy","family":"Zhang","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"He","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Zhan","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.","family":"Bauman","sequence":"additional","affiliation":[{"name":"Designer Drug Research Unit National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1541-3249","authenticated-orcid":false,"given":"Eliot L.","family":"Gardner","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6482-8104","authenticated-orcid":false,"given":"Zheng\u2010Xiong","family":"Xi","sequence":"additional","affiliation":[{"name":"Molecular Targets and Medications Discovery Branch National Institute on Drug Abuse, Intramural Research Program  Baltimore Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"issue":"457","key":"e_1_2_11_2_1","article-title":"Cannabinoid\u2010induced delayed gastric emptying is selectively increased upon intermittent administration in the rat: Role of CB1 receptors","volume":"23","author":"Abalo R.","year":"2011","journal-title":"Neurogastroenterology and Motility"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14748"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2010.00729.x"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2005.11.003"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12850"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/164_2018_144"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.5b00107"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0167965"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707527"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00211-9"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.08.017"},{"key":"e_1_2_11_13_1","first-page":"586","article-title":"In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): Inhibition of delta 9\u2010tetrahydrocannabinol\u2010induced responses and apparent agonist activity","volume":"277","author":"Compton D. 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