BACKGROUND AND PURPOSE:

Endogenous cannabinoids (endocannabinoids) in the periaqueductal gray (PAG) play a vital role in mediating stress-induced analgesia (SIA). This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific actions of endocannabinoids and their degradation inhibitors are largely unknown within this pain-modulating region.

EXPERIMENTAL APPROACH:

In vitro electrophysiological recordings were conducted from PAG neurons in rat midbrain slices. The actions of the major endocannabinoids and their degradation inhibitors were examined on inhibitory GABAergic synaptic transmission.

KEY RESULTS:

Exogenous application of the endocannabinoid, anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), produced a reduction in inhibitory GABAergic transmission in PAG neurons. The AEA-induced suppression of inhibition was enhanced by the fatty acid amide hydrolase (FAAH) inhibitor, URB597; while a 2-AG-induced suppression of inhibition was unmasked by the monoacylglycerol lipase (MAGL) inhibitor, JZL184. In addition, application of the CB1 receptor antagonist, AM251, produced a facilitation in basal GABAergic transmission in the presence of URB597 and JZL184, which was further enhanced in the dual FAAH/MAGL inhibitor, JZL195.

CONCLUSIONS AND IMPLICATIONS:

Our results indicate that AEA and 2-AG act via disinhibition within the PAG; a cellular action consistent with analgesia. These actions of AEA and 2-AG are tightly regulated by their respective degradative enzymes, FAAH and MAGL. Furthermore, individual or combined inhibition of FAAH and/or MAGL enhances tonic disinhibition within the PAG. Therefore, the current findings support the therapeutic potential of FAAH and MAGL inhibitors as a novel pharmacotherapy to treat pain.
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