Alpha-2 receptor mediates the endogenous antagonistic regulation of itch and pain via descending noradrenaline pathway from the locus coeruleus

Pain and itch are sensations that are regulated antagonistically; painful stimulation suppresses itch, while the inhibition of pain enhances itch. However, the central neural circuit underlying this antagonistic regulation remains elusive. The noradrenaline (NA) pathway from the locus coeruleus (LC) to the spinal cord (SC) constitutes an important component of endogenous descending pain inhibitory system. While the pathway of LC:SC has been extensively studied on pain modulation, its role in itch regulation remains poorly understood. We employed behavioral assays for itch and pain, immunofluorescence, electrophysiology, and chemogenetic techniques to investigate the role of noradrenergic (NAergic) neurons of LC (LC^NA neurons)and their pathways in modulating itch and pain. Our study has demonstrated that LC^NA neurons encode signals for both itch and pain. Inhibition of LC^NA neurons had no effect on itch but enhanced pain behaviour. Surprisingly, inhibition of the NAergic projection of LC:SC increased pain and suppressed itch. Furthermore, intrathecal injection of an α2 adrenergic receptor antagonist, but not α1 or β receptor antagonists, produced effects similar to those observed when the LC:SC pathway was inhibited. Our research suggests that the descending NAergic pathway from LC to SC exerts endogenous antagonistic regulation on itch and pain through α2 receptors.