Cellular and synaptic adaptations mediating opioid dependence

Physiol Rev. 2001 Jan;81(1):299-343. doi: 10.1152/physrev.2001.81.1.299.


Although opioids are highly effective for the treatment of pain, they are also known to be intensely addictive. There has been a massive research investment in the development of opioid analgesics, resulting in a plethora of compounds with varying affinity and efficacy at all the known opioid receptor subtypes. Although compounds of extremely high potency have been produced, the problem of tolerance to and dependence on these agonists persists. This review centers on the adaptive changes in cellular and synaptic function induced by chronic morphine treatment. The initial steps of opioid action are mediated through the activation of G protein-linked receptors. As is true for all G protein-linked receptors, opioid receptors activate and regulate multiple second messenger pathways associated with effector coupling, receptor trafficking, and nuclear signaling. These events are critical for understanding the early events leading to nonassociative tolerance and dependence. Equally important are associative and network changes that affect neurons that do not have opioid receptors but that are indirectly altered by opioid-sensitive cells. Finally, opioids and other drugs of abuse have some common cellular and anatomical pathways. The characterization of common pathways affected by different drugs, particularly after repeated treatment, is important in the understanding of drug abuse.

Publication types

  • Review

MeSH terms

  • Animals
  • Chronic Disease
  • Cyclic AMP / metabolism
  • Down-Regulation / drug effects
  • Drug Tolerance
  • Humans
  • Morphine / pharmacology*
  • Morphine Dependence / metabolism*
  • Nervous System / drug effects
  • Neuronal Plasticity / drug effects
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism*
  • Receptors, Opioid / metabolism
  • Second Messenger Systems / drug effects
  • Signal Transduction / drug effects
  • Synapses / drug effects
  • Synapses / metabolism
  • Synaptic Transmission / drug effects*


  • Receptors, Opioid
  • Morphine
  • Cyclic AMP