Capsaicin in the periaqueductal gray induces analgesia via metabotropic glutamate receptor-mediated endocannabinoid retrograde disinhibition

Br J Pharmacol. 2011 May;163(2):330-45. doi: 10.1111/j.1476-5381.2011.01214.x.


Background 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 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 and implications: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / pharmacology*
  • Animals
  • Arachidonic Acids / metabolism*
  • Capsaicin / pharmacology*
  • Cell Membrane / physiology
  • Endocannabinoids
  • Excitatory Postsynaptic Potentials
  • Glutamic Acid / metabolism
  • Glycerides / metabolism*
  • In Vitro Techniques
  • Inhibitory Postsynaptic Potentials
  • Lipoprotein Lipase / antagonists & inhibitors
  • Neurons / drug effects
  • Neurons / physiology
  • Pain Measurement
  • Patch-Clamp Techniques
  • Periaqueductal Gray / drug effects*
  • Periaqueductal Gray / physiology
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / physiology
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors
  • Receptors, Metabotropic Glutamate / physiology*
  • Signal Transduction / drug effects
  • Synaptic Transmission / drug effects
  • TRPV Cation Channels / agonists*
  • gamma-Aminobutyric Acid / metabolism


  • Analgesics
  • Arachidonic Acids
  • Endocannabinoids
  • Glycerides
  • Receptor, Cannabinoid, CB1
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • TRPV Cation Channels
  • Trpv1 protein, rat
  • metabotropic glutamate receptor type 1
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • glyceryl 2-arachidonate
  • Protein Kinase C
  • Lipoprotein Lipase
  • Capsaicin