Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

Catherine M. Cahill, Wendy Walwyn, Anna M.W. Taylor, Amynah A.A. Pradhan, Christopher J. Evans

Research output: Contribution to journalReview articlepeer-review

85 Scopus citations


Mechanisms of opioid tolerance have focused on adaptive modifications within cells containing opioid receptors, defined here as cellular allostasis, emphasizing regulation of the opioid receptor signalosome. We review additional regulatory and opponent processes involved in behavioral tolerance, and include mechanistic differences both between agonists (agonist bias), and between μ- and δ-opioid receptors. In a process we will refer to as pass-forward allostasis, cells modified directly by opioid drugs impute allostatic changes to downstream circuitry. Because of the broad distribution of opioid systems, every brain cell may be touched by pass-forward allostasis in the opioid-dependent/tolerant state. We will implicate neurons and microglia as interactive contributors to the cumulative allostatic processes creating analgesic and hedonic tolerance to opioid drugs.

Original languageEnglish
Pages (from-to)963-976
Number of pages14
JournalTrends in Pharmacological Sciences
Issue number11
StatePublished - Nov 1 2016


  • arrestin
  • bias signaling
  • dopamine
  • microglia
  • opponent processes
  • reward
  • μ opioid receptor


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