The noradrenergic pain regulation system: a potential target for pain therapy

Noradrenaline, through action on α₁- and α₂-adrenoceptors, is involved in intrinsic control of pain. Peripheral noradrenaline that is mainly released by the sympathetic nervous system has little influence on healthy tissues, whereas in injured or inflamed tissues it has varying effects, including aggravation of pain in neuropathy. The peripheral pronociceptive effect has been associated with injury-induced expression of novel noradrenergic receptors, sprouting of sympathetic nerve fibers, and pronociceptive changes in the ion channel properties on primary afferent nociceptors, whereas an interaction with the immune system may contribute to peripheral antinociceptive effect of noradrenaline. In the spinal dorsal horn, noradrenaline released from descending pathways originating in the pontine A5-A7 cell groups attenuates pain by inhibitory action on α(2A)-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct α₂-adrenergic action on spinal pain-relay neurons (postsynaptic inhibition), and by α₁-adrenergic activation of inhibitory interneurons. Moreover, α(2C)-adrenoceptors on axon terminals of excitatory interneurons might contribute to spinal control of pain. At supraspinal levels, the effect of noradrenergic system on pain has varied depending on many factors such as the type of the adrenoceptor, pathophysiological condition, and the brain area. In general, the baseline pain sensitivity is only little influenced by the noradrenergic system, whereas in injured conditions the noradrenergic system contributes to feedback inhibition of pain. The central as well as the peripheral noradrenergic system is subject to various plastic changes following injury or inflammation that influence its antinociceptive efficiency. α₂-Adrenoceptor agonists have proven effective in treating various pain conditions.