Activation of type 5 metabotropic glutamate receptors and diacylglycerol lipase-α initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia

Laura C. Gregg, Kwang Mook Jung, Jessica M. Spradley, Rita Nyilas, Richard L. Suplita, Andreas Zimmer, Masahiko Watanabe, Ken Mackie, István Katona, Daniele Piomelli, Andrea G. Hohmann

Research output: Article

56 Citations (Scopus)

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-sn-glycerol (2-AG) in controlling pain sensitivity in vivo. Here, we show that footshock stress produces antinociception in rats by activating type 5 metabotropic glutamate receptors (mGlu 5) in the dorsolateral periaqueductal gray (dlPAG) and mobilizing 2-AG. Stimulation of mGlu 5 in the dlPAG with DHPG [(S)-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 CB 1 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-αand 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 mGlu 5 at postsynaptic sites of the dlPAG, whereas CB 1 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 mGlu 5-DGL-α cascade triggers retrograde 2-AG signaling in vivo. This pathway is required for endocannabinoid-mediated stress-induced analgesia.

Original languageEnglish
Pages (from-to)9457-9468
Number of pages12
JournalJournal of Neuroscience
Volume32
Issue number28
DOIs
Publication statusPublished - júl. 11 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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    Gregg, L. C., Jung, K. M., Spradley, J. M., Nyilas, R., Suplita, R. L., Zimmer, A., Watanabe, M., Mackie, K., Katona, I., Piomelli, D., & Hohmann, A. G. (2012). Activation of type 5 metabotropic glutamate receptors and diacylglycerol lipase-α initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia. Journal of Neuroscience, 32(28), 9457-9468. https://doi.org/10.1523/JNEUROSCI.0013-12.2012