title: Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Capsaicin (1-10 µM) 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 CB₁ and metabotropic glutamate (mGlu₅) 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 CB₁ and mGlu receptor antagonists. Effects of capsaicin were antagonized by SB 366791, a TRPV1 channel antagonist.
  
  
  CONCLUSIONS
  Capsaicin activated TRPV1s on glutamatergic terminals to release glutamate which activated postsynaptic mGlu₅ receptors, yielding 2-AG from DAG by DAGL hydrolysis. 2-AG induces retrograde inhibition (disinhibition) of GABA release via presynaptic CB₁ 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.
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-T
authors.initials: HT
authors.lastname: Liao
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lee
authors.forename: Y-C
authors.initials: YC
authors.lastname: Ho
authors.forename: L-C
authors.initials: LC
authors.lastname: Chiou
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology*; D002462:Cell Membrane / Q000502:physiology; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials; D018698:Glutamic Acid / Q000378:metabolism; D005989:Glycerides / Q000378:metabolism*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D008071:Lipoprotein Lipase / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000187:drug effects* / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000502:physiology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D050916:TRPV Cation Channels / Q000819:agonists*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000700:Analgesics; D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D011493:Protein Kinase C; D008071:Lipoprotein Lipase; D002211:Capsaicin