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Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition Liao HT; Lee HJ; Ho YC; Chiou LCBr J Pharmacol 2011[May]; 163 (2): 330-45BACKGROUND AND PURPOSE: Capsaicin, an agonist of transient receptor potential vanilloid 1 (TRPV1) channels, is pro-nociceptive in the periphery but is anti-nociceptive when administered into the ventrolateral periaqueductal gray (vlPAG), a midbrain region for initiating descending pain inhibition. Here, we investigated how activation of TRPV1 channels in the vlPAG leads to anti-nociception. EXPERIMENTAL APPROACH: We examined synaptic transmission and neuronal activity using whole-cell recordings in vlPAG slices in vitro and hot-plate nociceptive responses in rats after drug microinjection into the vlPAG in vivo. KEY RESULTS: Capsaicin (1-10 microM) depressed evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in vlPAG slices presynaptically, while increasing miniature excitatory PSC frequency. Capsaicin-induced eIPSC depression was antagonized by cannabinoid CB(1) and metabotropic glutamate (mGlu(5)) receptor antagonists, and prevented by inhibiting diacylglycerol lipase (DAGL), which converts DAG into 2-arachidonoylglycerol (2-AG), an endocannabinoid. Capsaicin induced membrane depolarization in 2/3 neurons recorded but, overall, increased neuronal firings by increasing evoked postsynaptic potentials. Intra-vlPAG capsaicin reduced hot-plate responses in rats, effects blocked by CB(1) and mGlu receptor antagonists. Effects of capsaicin were antagonized by SB 366791, a TRPV1 channel antagonist. CONCLUSIONS AND IMPLICATIONS: Capsaicin activated TRPV1s on glutamatergic terminals to release glutamate which activated postsynaptic mGlu(5) receptors, yielding 2-AG from DAG by DAGL hydrolysis. 2-AG induces retrograde inhibition (disinhibition) of GABA release via presynaptic CB(1) receptors. This disinhibition in the vlPAG leads to anti-nociception by activating the descending pain inhibitory pathway. This is a novel TRPV1 channel-mediated anti-nociceptive mechanism in the brain and a new interaction between vanilloid and endocannabinoid systems.|Analgesics/*pharmacology[MESH]|Animals[MESH]|Arachidonic Acids/*metabolism[MESH]|Capsaicin/*pharmacology[MESH]|Cell Membrane/physiology[MESH]|Endocannabinoids[MESH]|Excitatory Postsynaptic Potentials[MESH]|Glutamic Acid/metabolism[MESH]|Glycerides/*metabolism[MESH]|In Vitro Techniques[MESH]|Inhibitory Postsynaptic Potentials[MESH]|Lipoprotein Lipase/antagonists & inhibitors[MESH]|Neurons/drug effects/physiology[MESH]|Pain Measurement[MESH]|Patch-Clamp Techniques[MESH]|Periaqueductal Gray/*drug effects/physiology[MESH]|Protein Kinase C/metabolism[MESH]|Rats[MESH]|Rats, Wistar[MESH]|Receptor, Cannabinoid, CB1/antagonists & inhibitors/physiology[MESH]|Receptor, Metabotropic Glutamate 5[MESH]|Receptors, Metabotropic Glutamate/antagonists & inhibitors/*physiology[MESH]|Signal Transduction/drug effects[MESH]|Synaptic Transmission/drug effects[MESH]|TRPV Cation Channels/*agonists[MESH]|gamma-Aminobutyric Acid/metabolism[MESH] |