The origin of diffuse noxious inhibitory controls

Pain alerts us to actual or potential tissue damage. During acute pain, our central nervous system acts endogenously to modulate pain processing, thus reducing or enhancing pain perception. However, during chronic pain, the balance between inhibitory and facilitatory processes are tipped in favour of pro-pain modulation. Diffuse noxious inhibitory controls (DNIC) is a naturally occurring pain inhibitory pathway that projects from the brainstem to the spinal cord to inhibit neuronal activity therein in a manner that is 1) subserved by noradrenaline, and 2) dysfunctional in chronicity. To harness its high therapeutic potential, we aimed to anatomically and functionally define DNIC. Through employing an intersectional opto- and chemogenetic approach to modulate activity in brainstem noradrenergic nuclei, here we show that spinal neuronal firing observed upon DNIC activation during electrophysiological experiments, and animal pain thresholds observed during behavioural experiments, are modulated in a pro-pain manner upon opto-manipulation of A5 spinally projecting noradrenergic neurons, thus evidencing the DNIC origin. Given the plasticity of the functional expression of DNIC in disease, and the success of back and forward translation of paradigms that evoke DNIC in pre-clinical and clinical models, our findings offer an attractive avenue of studies for disease specific analgesic interventions. ### Competing Interest Statement The authors have declared no competing interest.