Control of RVM to spinal cord pain descending pathway by vlPAG-SST neurons in a physiopathological context

Pain is an adaptive and primordial aspect of mammal’s physiology whose role is to warn against potential harmful situations and prevent aggravation of actual physical damages. However, many patients suffer from chronic pain, which overpasses pain’s adaptive trait becoming pathological. Nociceptive signal transmission is first relayed by the spinal cord before reaching the brain through ascending pathways. The control of spinal integration descending pathway is orchestrated by the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). In the RVM, ON, OFF and neutral cells, are respectively activated, inhibited, unchanged during nociceptive responses. Moreover, the somatostatin neurons of the vlPAG are known to be involved in spinal hypersensitivity to nociceptive inputs but their underlying circuits are still unknown. Here, we hypothesize that vlPAG-SST neurons project to the RVM and activate ON and inhibit OFF cells. We coupled electrophysiology and optogenetic tools to manipulate and record this pathway during nociceptive stimulation in freely moving animals. Our results first confirm that vlPAG-SST terminal activation in the RVM induces mechanical allodynia and thermal hyperalgesia and elicits a response in ON and OFF cells during innocuous stimulation. Then, we used a chronic pain model (SNI), and show that unexpectedly, the same manipulation alleviates mechanical allodynia, while the different RVM neurons exhibit altered responses during noxious stimulation. This work emphasizes that vlPAG-SST neurons modulate ON and OFF cells activity and that this circuitry is altered in pathological conditions. It suggests that acknowledging descending circuitry plasticity is crucial when developing new therapeutics in chronic pain.