Opioid-induced central immune signaling: implications for opioid analgesia

Headache. 2015 Apr;55(4):475-89. doi: 10.1111/head.12552. Epub 2015 Mar 31.


Despite being the mainstay of pain management, opioids are limited in their clinical utility by adverse effects, such as tolerance and paradoxical hyperalgesia. Research of the past 15 years has extended beyond neurons, to implicate central nervous system immune signaling in these adverse effects. This article will provide an overview of these central immune mechanisms in opioid tolerance and paradoxical hyperalgesia, including those mediated by Toll-like receptor 4, purinergic, ceramide, and chemokine signaling. Challenges for the future, as well as new lines of investigation will be highlighted.

Keywords: P2X4 receptor; P2X7 receptor; TLR4; allodynia; hyperalgesia; opioid receptor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Analgesia / adverse effects
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Central Nervous System / drug effects
  • Central Nervous System / immunology*
  • Drug Tolerance / immunology*
  • Humans
  • Hyperalgesia / chemically induced
  • Hyperalgesia / immunology
  • Signal Transduction / drug effects
  • Signal Transduction / immunology*
  • Toll-Like Receptor 4 / immunology


  • Analgesics, Opioid
  • TLR4 protein, human
  • Toll-Like Receptor 4