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Our previous studies demonstrated that genetic deletion of CB2 inhibits microglial activation during inflammatory stimulation of toll-like receptors (TLRs) or in neurodegenerative conditions. However, we cannot exclude developmental effects of the constitutive CB2 knockout (CB2<jats:sup>\u2212\/\u2212<\/jats:sup>), which could mediate compensatory outcomes in CB2<jats:sup>\u2212\/\u2212<\/jats:sup> mice. In the present study, we therefore tested whether acute pharmacological inhibition of CB2 receptor has a similar effect on microglial activation as in CB2<jats:sup>\u2212\/\u2212<\/jats:sup> in response to inflammatory stimulation. Our findings suggest that the CB2-specific antagonist SR144528 has little or no effect on LPS\/IFN-\u03b3-induced activation in primary microglia or organotypic hippocampal slice cultures at nanomolar concentrations. We show that SR144528 did not alter LPS\/IFN-\u03b3-mediated microglial cytokine secretion, Iba1 and CD68 staining intensity or morphology at 1 and 10\u00a0nM. Although SR144528 suppressed LPS\/IFN-\u03b3-induced microglial activation at 1\u00a0\u00b5M, this anti-inflammatory effect was not dependent on CB2 receptors and exceeded the Ki on CB2 receptors by more than a thousand-fold. Thus, SR144528 does not mimic the anti-inflammatory effects observed in the CB2<jats:sup>\u2212\/\u2212<\/jats:sup> microglia after LPS\/IFN-\u03b3 stimulation. Therefore, we propose that the deletion of CB2 probably triggered an adaptive mechanism, making microglia less responsive to inflammatory stimulation.<\/jats:p>","DOI":"10.1038\/s41598-023-37702-z","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T10:02:42Z","timestamp":1688983362000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Pharmacological blockade of cannabinoid receptor 2 signaling does not affect LPS\/IFN-\u03b3-induced microglial activation"],"prefix":"10.1038","volume":"13","author":[{"given":"Bolanle Fatimat","family":"Olabiyi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Caroline","family":"Schmoele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva Carolina","family":"Beins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Zimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,7,10]]},"reference":[{"key":"37702_CR1","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1054\/plef.2001.0341","volume":"66","author":"RG Pertwee","year":"2002","unstructured":"Pertwee, R. 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