NeuroImmune Transmitters: Norepinephrine

It is becoming clear that neurotransmitters play a greater role in the immune system than previously thought.  Norepinephrine is a catecholamine with multiple roles including acting as a hormone and neurotransmitter.  It is best known for its role in the fight-or-flight stress response along with epinephrine, but its role in modulating neuroinflammation is just becoming better understood.  Below are reviews of studies that have uncovered some of norepinephrine’s immunomodulatory effects.

  • Rommelfanger, et al. (2007) report that norepinephrine suppresses the expression of proinflammatory molecules, such as TNF- α and IL-1β, and elevates the expression of anti-inflammatory molecules, such as IκB, by signaling through α1-, α2-, and β-adrenergic receptors on astrocytes and glia.  This regulates expression of inflammatory genes and nitric oxide (NO), which are thought to contribute to neurodegenerative diseases.
  • A study by Takayanagi, et al. (2012) has found that norepinephrine regulate intestinal mucosal immune responses.  Norepinephrine suppresses the production of IFN-γ and TNF-α in murine intestinal intraepithelial lymphocytes via the β1 adrenoceptor in murines.
  • The 2003 review by Pavlov, et al. also discusses the impact of norepinephrine on the immune system.  A major noradrenergic center of the brain is the locus coeruleus (LC), which signals to sympathetic preganglionic cholinergic neurons in the spinal cord.  Some of these sympathetic nerve endings release norepinephrine, which has been found to have anti-inflammatory effects by interacting with the adrenoceptors expressed on lymphocytes and macrophages.  In this way, norepinephrine has activity at both ends of the pathway: initiating the signaling from the LC and interacting with the immune adrenoceptors to have an immunomodulatory effect.

Norepinephrine’s role in modulating the immune system and more specifically, neuroinflammation, should be considered when reviewing a urinary neurotransmitter test result.  It is not uncommon to see elevated urinary norepinephrine levels in patients with acute or chronic inflammation or with an active immune system.  Potential causes of inflammation should be considered when elevated norepinephrine levels are found, especially if a patient presents with persistently elevated levels.

Pavlov, V.A., Wang, H., Czura, C.J., Griedman, S.G., and Tracey, K.J. (2003). The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation. Molecular Medicine, 9(5-8):125-34.
Rommelfanger, K.S., Weinshender, D. (2007). Norepinephrine: The redheaded stepchild of Parkinson’s disease. Biochemical Pharmacology, 74(2):177-90.
Takayanagi, Y., Osawa, S., Ikuma, M., Takagaki, K., Zhang, J., Jamaya, Y., Yamada, T., Sugimoto M., Furuta, T., Miyajima, H., Sugimoto, K. (2012). Norepinephrine suppresses INF-γ and TNF-α production by murine intestinal intraepithelial lymphocytes via the β1 adrenoceptor. Journal of Neuroimmunology, 245(1-2):66-74.
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