BRAINSTEM TO DORSAL HORN PATHWAY CONNECTIVITY SHED LIGHT ON THE PAIN DESCENDING PATHWAY DYNAMICS IN PHYSIOLOGICAL AND PATHOLOGICAL PAIN

Pain is an adaptive and primordial aspect of mammal’s physiology warning against potential harmful situations and preventing 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 descending spinal integration is orchestrated by the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM). Neuronal actors like the somatostatin cells (SST) of the vlPAG are known to promote hypersensitivity, and the RVM ON, OFF, and neutral cells are described by their pronociceptive, antinociceptive and neutral roles in sending information to the dorsal horn of the spinal cord (DHSC). However, little is known about the precise connectivity of this pathway in normal and pathological pain. In this study we hypothesized that the vlPAG-SST neurons target RVM cells in a structured manner to relay pain sensitivity in the DHSC, in a physio/pathological context. First, with an anatomical approach we show that SST-vlPAG outputs target the serotonin (5HT) cells of the RVM, projecting in turn to the DHSC. Furthermore, the manipulation and recording of the pathway with optogenetic, pharmacological and electrophysiology in anesthetized mice shows evidence of inhibitory targeting on the WDR of the DHSC. Finally, our results show that activating SST-vlPAG RVM inputs increases DHSC activity upon nociceptive paw stimulation, but decreases in chronic pain. This work shed light on pain descending spinal integration connectivity, highlighting the SSt-vlPAG-5HT-RVM-DHSC pathway relaying differential information in a physiopathological context.