Neurobiology of opioid withdrawal: Role of the endothelin system

Life Sci. 2016 Aug 15;159:34-42. doi: 10.1016/j.lfs.2016.01.016. Epub 2016 Jan 13.


Morphine and oxycodone are potent opioid analgesics most commonly used for the management of moderate to severe acute and chronic pain. Their clinical utility is limited by undesired side effects like analgesic tolerance, dependence, and withdrawal. We have previously demonstrated that endothelin-A (ETA) receptor antagonists potentiate opioid analgesia and eliminate analgesic tolerance. Mechanistically, G proteins and regulatory proteins such as β-arrestins have shown to play an important role in mediating opioid tolerance, dependence, and withdrawal. Recently, the involvement of central ET mechanisms in opioid withdrawal was investigated. ETA receptor antagonist was shown to block majority of the signs and symptoms associated with opioid withdrawal. This review focuses on ET as one of the potential novel strategies to manage the challenge of opioid withdrawal. An overview of additional players in this process (G proteins and β-arrestin2), and the possible therapeutic implications of these findings are presented.

Keywords: BQ123; Endothelin ET(A) receptor antagonist; G protein coupled receptor (GPCR); Morphine; Nerve growth factor (NGF); Oxycodone; Withdrawal; β-Arrestin 2.

Publication types

  • Review

MeSH terms

  • Central Nervous System / metabolism
  • Drug Tolerance
  • Endothelins / physiology*
  • Humans
  • Opioid-Related Disorders / physiopathology*
  • Receptors, Endothelin / physiology
  • Substance Withdrawal Syndrome / physiopathology*
  • Substance Withdrawal Syndrome / therapy


  • Endothelins
  • Receptors, Endothelin