Fig. 8.

A proposed schema illustrating how NPS, orexins, substance P, mGlu₅R and endocannabinoid (2-AG) may be involved in SIA. Before stress, the projection neurons in the vlPAG is under GABAergic inhibitory control. During stress, hypothalamic orexin neurons (OX) are activated by NPS, which is released possibly from the NPS neurosn in peri-LC and/or the KF-PBN in mice [24], releasing orexins that activate the OX₁Rs on neurokinin (SubP) neurons and release substance P in the vlPAG. Then, substance P activates the NK₁R-containing glutamate (Glu) neurons, yielding massive glutamate that in turn activates perisynaptic mGlu₅Rs to initiate the GqPCR signalling and generate 2-AG. This endocannabinoid then retrogradely activates presynaptic CB₁Rs to inhibit GABA release in the vlPAG, ultimately leading to analgesia. The points of pharmacological intervention performed in this study are marked with blunt arrows, labelled with the respective antagonists. The images of neurons are adapted from Illustration Toolkit Neuroscience by Motifolio. PN: projection neuron. GABA_AR: GABA_A receptor