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• W2092439632 abstract "Acute stress reduces pain sensitivity by engaging an endocannabinoid signaling circuit in the midbrain. The neural mechanisms governing this process and molecular identity of the endocannabinoid substance(s) involved are unknown. We combined behavior, pharmacology, immunohistochemistry, RNA interference, quantitative RT-PCR, enzyme assays, and lipidomic analyses of endocannabinoid content to uncover the role of the endocannabinoid 2-arachidonoyl-<i>sn</i>-glycerol (2-AG) in controlling pain sensitivity <i>in vivo</i>. Here, we show that footshock stress produces antinociception in rats by activating type 5 metabotropic glutamate receptors (mGlu₅) in the dorsolateral periaqueductal gray (dlPAG) and mobilizing 2-AG. Stimulation of mGlu₅ in the dlPAG with DHPG [(<i>S</i>)-3,5-dihydroxyphenylglycine] triggered 2-AG formation and enhanced stress-dependent antinociception through a mechanism dependent upon both postsynaptic diacylglycerol lipase (DGL) activity, which releases 2-AG, and presynaptic CB₁ cannabinoid receptors. Pharmacological blockade of DGL activity in the dlPAG with RHC80267 [1,6-bis(cyclohexyloximinocarbonylamino)hexane] and (−)-tetrahydrolipstatin (THL), which inhibit activity of DGL-α and DGL-β isoforms, suppressed stress-induced antinociception. Inhibition of DGL activity in the dlPAG with THL selectively decreased accumulation of 2-AG without altering levels of anandamide. The putative 2-AG-synthesizing enzyme DGL-α colocalized with mGlu₅ at postsynaptic sites of the dlPAG, whereas CB₁ was confined to presynaptic terminals, consistent with a role for 2-AG as a retrograde signaling messenger. Finally, virally mediated silencing of DGL-α, but not DGL-β, transcription in the dlPAG mimicked effects of DGL inhibition in suppressing both endocannabinoid-mediated stress antinociception and 2-AG formation. The results indicate that activation of the postsynaptic mGlu₅–DGL-α cascade triggers retrograde 2-AG signaling <i>in vivo</i>. This pathway is required for endocannabinoid-mediated stress-induced analgesia." @default.
• W2092439632 created "2016-06-24" @default.
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• W2092439632 date "2012-07-11" @default.
• W2092439632 modified "2023-10-14" @default.
• W2092439632 title "Activation of Type 5 Metabotropic Glutamate Receptors and Diacylglycerol Lipase- Initiates 2-Arachidonoylglycerol Formation and Endocannabinoid-Mediated Analgesia" @default.
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• W2092439632 doi "https://doi.org/10.1523/jneurosci.0013-12.2012" @default.
• W2092439632 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3652685" @default.
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