The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. (Suarez et al, 2022)
LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α₁-adrenoceptors and inhibition by α₂-adrenoceptors. (Szabadi, 2013)
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. Interaction with the immune system may contribute to peripheral antinociceptive effect of noradrenaline. 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. (Pertovaara, 2013)
Suárez-Pereira I, Llorca-Torralba M, Bravo L, Camarena-Delgado C, Soriano-Mas C, Berrocoso E. The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders. Biol Psychiatry. 2022 May 1;91(9):786-797. doi: 10.1016/j.biopsych.2021.11.023. Epub 2021 Dec 16. PMID: 35164940.
Szabadi E. Functional neuroanatomy of the central noradrenergic system. J Psychopharmacol. 2013 Aug;27(8):659-93. doi: 10.1177/0269881113490326. Epub 2013 Jun 12. Erratum in: J Psychopharmacol. 2013 Oct;27(10):964. PMID: 23761387.
Pertovaara A. The noradrenergic pain regulation system: a potential target for pain therapy. Eur J Pharmacol. 2013 Sep 15;716(1-3):2-7. doi: 10.1016/j.ejphar.2013.01.067. Epub 2013 Mar 13. PMID: 23500194.