Noradrenergic pain modulation.

Norepinephrine is involved in intrinsic control of pain. Main sources of norepinephrine are sympathetic nerves peripherally and noradrenergic brainstem nuclei A1-A7 centrally. Peripheral norepinephrine has little influence on pain in healthy tissues, whereas in injured tissues it has variable effects, including aggravation of pain. Its peripheral pronociceptive effect has been associated with injury-induced expression of novel noradrenergic receptors, sprouting of sympathetic nerve fibers, and pronociceptive changes in the ionic channel properties of primary afferent nociceptors, while an interaction with the immune system may contribute in part to peripheral antinociception induced by norepinephrine. In the spinal cord, norepinephrine released from descending pathways suppresses pain by inhibitory action on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct alpha-2-adrenergic action on pain-relay neurons (postsynaptic inhibition), and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Additionally, alpha-2C-adrenoceptors on axon terminals of excitatory interneurons of the spinal dorsal horn possibly contribute to spinal control of pain. At supraspinal levels, the pain modulatory effect by norepinephrine and noradrenergic receptors has varied depending on many factors such as the supraspinal site, the type of the adrenoceptor, the duration of the pain and pathophysiological condition. While in baseline conditions the noradrenergic system may have little effect, sustained pain induces noradrenergic feedback inhibition of pain. Noradrenergic systems may also contribute to top-down control of pain, such as induced by a change in the behavioral state. Following injury or inflammation, the central as well as peripheral noradrenergic system is subject to various plastic changes that influence its antinociceptive efficacy.