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Activation of type 5 metabotropic glutamate receptors and diacylglycerol lipase-α initiates 2-arachidonoylglycerol formation and endocannabinoid-mediated analgesia.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2012 Jul 11; Vol. 32 (28), pp. 9457-68. - Publication Year :
- 2012
-
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-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 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.
- Subjects :
- Analysis of Variance
Animals
Cannabinoid Receptor Modulators agonists
Cannabinoid Receptor Modulators antagonists & inhibitors
Cyclohexanones pharmacology
Dose-Response Relationship, Drug
Electroconvulsive Therapy methods
Excitatory Amino Acid Antagonists pharmacology
Male
Methoxyhydroxyphenylglycol administration & dosage
Methoxyhydroxyphenylglycol analogs & derivatives
Mice
Microscopy, Immunoelectron
Pain drug therapy
Pain pathology
Periaqueductal Gray drug effects
Periaqueductal Gray metabolism
Piperidines pharmacology
Protease Inhibitors pharmacology
Pyrazoles pharmacology
Pyridines pharmacology
RNA, Messenger metabolism
RNA, Small Interfering therapeutic use
Rats
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1 metabolism
Receptor, Metabotropic Glutamate 5
Rimonabant
Synapses metabolism
Synapses ultrastructure
Tandem Mass Spectrometry
Analgesia methods
Arachidonic Acids metabolism
Cannabinoid Receptor Modulators pharmacology
Endocannabinoids
Glycerides metabolism
Lipoprotein Lipase metabolism
Pain metabolism
Receptors, Metabotropic Glutamate metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 32
- Issue :
- 28
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 22787031
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.0013-12.2012