Cellular neuroadaptations to chronic opioids: tolerance, withdrawal and addiction

Br J Pharmacol. 2008 May;154(2):384-96. doi: 10.1038/bjp.2008.100. Epub 2008 Apr 14.


A large range of neuroadaptations develop in response to chronic opioid exposure and these are thought to be more or less critical for expression of the major features of opioid addiction: tolerance, withdrawal and processes that may contribute to compulsive use and relapse. This review considers these adaptations at different levels of organization in the nervous system including tolerance at the mu-opioid receptor itself, cellular tolerance and withdrawal in opioid-sensitive neurons, systems tolerance and withdrawal in opioid-sensitive nerve networks, as well as synaptic plasticity in opioid sensitive nerve networks. Receptor tolerance appears to involve enhancement of mechanisms of receptor regulation, including desensitization and internalization. Adaptations causing cellular tolerance are more complex but several important processes have been identified including upregulation of cAMP/PKA and cAMP response element-binding signalling and perhaps the mitogen activated PK cascades in opioid sensitive neurons that might not only influence tolerance and withdrawal but also synaptic plasticity during cycles of intoxication and withdrawal. The potential complexity of network, or systems adaptations that interact with opioid-sensitive neurons is great but some candidate neuropeptide systems that interact with mu-opioid sensitive neurons may play a role in tolerance and withdrawal, as might activation of glial signalling. Implication of synaptic forms of learning such as long term potentiation and long term depression in opioid addiction is still in its infancy but this ultimately has the potential to identify specific synapses that contribute to compulsive use and relapse.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptation, Physiological
  • Adenylyl Cyclases / metabolism
  • Analgesics, Opioid / adverse effects*
  • Animals
  • Behavior, Addictive / metabolism*
  • Behavior, Addictive / physiopathology
  • Brain / drug effects*
  • Brain / enzymology
  • Brain / metabolism
  • Brain / physiopathology
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Drug Tolerance*
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Neural Pathways / drug effects
  • Neural Pathways / metabolism
  • Neuronal Plasticity / drug effects
  • Opioid-Related Disorders / metabolism*
  • Opioid-Related Disorders / physiopathology
  • Opioid-Related Disorders / psychology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Receptors, Opioid, mu / drug effects
  • Receptors, Opioid, mu / metabolism
  • Signal Transduction / drug effects
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / physiopathology
  • Substance Withdrawal Syndrome / psychology
  • Synaptic Transmission / drug effects


  • Analgesics, Opioid
  • Receptors, Opioid, mu
  • Cyclic AMP
  • Phosphatidylinositol 3-Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Adenylyl Cyclases