What are the mechanisms of tolerance and withdrawal in opioid abuse?

Updated: Jun 21, 2018
  • Author: David W Dixon, DO; Chief Editor: Glen L Xiong, MD  more...
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Mechanisms of tolerance and withdrawal include but are not limited to the following:

  • In response to long-term exposure to relatively high doses of exogenous opioids, cells internalize their mu and delta opioid receptors. Therefore, increased opioid levels and/or increased opioid potency are necessary to generate the same effect on fewer receptors (tolerance). Similarly, once the exogenous opioids are removed from the system, the remaining endogenous opioids are unable to sufficiently activate the small number of remaining receptors (withdrawal).

  • Intracellular second-messenger systems mediating the activity of opioid receptors are down-regulated in the presence of high levels of potent exogenous opioids. Therefore, even the few remaining opioid receptors cannot generate the response they were capable of prior to the administration of exogenous opioids. Down-regulated second messengers include G-proteins and adenylyl cyclase/cAMP.

  • Acute tolerance can be mediated by changes in the phosphorylation patterns of mu and delta opiod receptors.

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