Figure 8.
Proposed model for substance P-induced suppression of GABAergic transmission in the PAG. Substance P (SubP) activates NK1, NK2, and NK3 (NK1–3) receptors located on glutamatergic (GLU) neurons to elicit action potential (AP) generation via the opening of a nonselective cation conductance (Icat) and suppression of a G-protein-coupled inwardly rectifying K+ (GIRK) conductance (Drew et al., 2005). The resultant action potential-driven glutamate release is sufficient to overwhelm neuronal glutamate transporters, presumably excitatory amino acid carrier 1 (EAAC1) (Drew et al., 2008), and engage postsynaptic mGluR5s. Synthesis of the endocannabinoid 2-AG subsequently occurs via catalysis of diacylglycerol by a 1,2-diacylglycerol lipase (DAGL). 2-AG then acts as a retrograde messenger to activate presynaptic CB1Rs located on the terminals of GABAergic neurons and to reduce GABA release. Activation of this dual excitatory and disinhibitory mechanism in PAG-RVM projection neurons would be predicted to then facilitate activation of this descending pathway.