Article date: May 2011
By: H‐T Liao, H‐J Lee, Y‐C Ho, L‐C Chiou in Volume 163, Issue 2, pages 330-345
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.
DOI: 10.1111/j.1476-5381.2011.01214.x
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