Targeted inactivation of spinal α2 adrenoceptors promotes paradoxical anti-nociception

Noradrenergic drive from the brainstem to the spinal cord varies in a context-dependent manner to regulate the patterns of sensory and motor transmission that govern perception and action. In sensory networks, it is traditionally assumed that activation of spinal α2 receptors is anti-nociceptive, while spinal α2 blockade is pro-nociceptive. Here, however, we demonstrate in vivo in rats that targeted blockade of spinal α2 receptors can promote anti-nociception. The anti-nociceptive effects are not contingent upon supraspinal actions, as they persist below a chronic spinal cord injury and are enhanced by direct spinal application of antagonist. They are also evident throughout sensory-dominant, sensorimotor integrative, and motor-dominant regions of the gray matter, and neither global changes in spinal neural excitability nor off-target activation of spinal α1 adrenoceptors or 5HT_1A receptors abolished the anti-nociception. Together, these findings challenge the current understanding of noradrenergic modulation of spinal nociceptive transmission.