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 2 receptors is anti-nociceptive, while spinal 2 blockade is pro-nociceptive. Here, however, we demonstrate in vivo in rats that targeted blockade of spinal 2 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 1 adrenoceptors or 5HT1A receptors abolished the anti-nociception. Together, these findings challenge the current understanding of noradrenergic modulation of spinal nociceptive transmission.