Group I metabotropic glutamate receptors modulate endocannabinoid-mediated stress-induced analgesia

Abstract

Stress-induced analgesia (SIA) is mediated by mobilization of endocannabinoid lipids such as 2-arachidonoylglycerol (2-AG) in the midbrain periaqueductal gray (PAG). 2-AG may be synthesized on demand to induce SIA through the consecutive activation of two enzymes- phospholipase C (PLC) and diacylglycerol lipase (DGL). We examined whether activation of postsynaptic group I metabotropic glutamate receptors (mGluRs) would enhance SIA because of their known coupling to PLC. Microinjection of the group I mGluR agonist DHPG into the dorsolateral PAG (dPAG) enhanced SIA through a CB1-dependent mechanism. Microinjection of the DGL inhibitors tetrahydrolipstatin (THL) and RHC80267 into the dPAG suppressed SIA. The DHPG-induced enhancement of SIA was blocked by THL. Off-site injections of the active compounds did not alter SIA. Our results support the hypothesis that exposure to environmental stressors stimulates synthesis of 2-AG through the PLC/DGL pathway to induce SIA. Moreover, this process may be initiated by activation of group I mGluRs.