Strategies to Treat Chronic Pain and Strengthen Impaired Descending Noradrenergic Inhibitory System

Int J Mol Sci. 2019 Feb 14;20(4):822. doi: 10.3390/ijms20040822.


Gabapentinoids (gabapentin and pregabalin) and antidepressants (tricyclic antidepressants and serotonin noradrenaline reuptake inhibitors) are often used to treat chronic pain. The descending noradrenergic inhibitory system from the locus coeruleus (LC) to the dorsal horn of the spinal cord plays an important role in the analgesic mechanisms of these drugs. Gabapentinoids activate the LC by inhibiting the release of γ-aminobutyric acid (GABA) and inducing the release of glutamate, thereby increasing noradrenaline levels in the spinal cord. Antidepressants increase noradrenaline levels in the spinal cord by inhibiting reuptake, and accumulating noradrenaline inhibits chronic pain through α₂-adrenergic receptors in the spinal cord. Recent animal studies, however, revealed that the function of the descending noradrenergic inhibitory system is impaired in chronic pain states. Other recent studies found that histone deacetylase inhibitors and antidepressants restore the impaired noradrenergic descending inhibitory system acting on noradrenergic neurons in the LC.

Keywords: descending inhibition; hypersensitivity; locus coeruleus; neuropathic pain; noradrenaline; rats; spinal cord; α2-adrenergic receptors.

Publication types

  • Review

MeSH terms

  • Animals
  • Antidepressive Agents, Tricyclic / administration & dosage
  • Chronic Pain / drug therapy*
  • Chronic Pain / genetics
  • Chronic Pain / physiopathology
  • GABA Antagonists / administration & dosage
  • GABA Antagonists / metabolism
  • Gabapentin / administration & dosage
  • Humans
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / physiopathology
  • Norepinephrine / antagonists & inhibitors*
  • Norepinephrine / genetics
  • Norepinephrine / metabolism
  • Pregabalin / administration & dosage
  • Receptors, Adrenergic, alpha-2 / genetics*
  • Selective Serotonin Reuptake Inhibitors / administration & dosage*
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / physiopathology
  • Spinal Cord Dorsal Horn / drug effects
  • Spinal Cord Dorsal Horn / physiopathology


  • Antidepressive Agents, Tricyclic
  • GABA Antagonists
  • Receptors, Adrenergic, alpha-2
  • Serotonin Uptake Inhibitors
  • Pregabalin
  • Gabapentin
  • Norepinephrine