Discovery of a novel site of opioid action at the innate immune pattern-recognition receptor TLR4 and its role in addiction

Int Rev Neurobiol. 2014;118:129-63. doi: 10.1016/B978-0-12-801284-0.00006-3.


Opioids have historically, and continue to be, an integral component of pain management. However, despite pharmacokinetic and dynamic optimization over the past 100 years, opioids continue to produce many undesirable side effects such as tolerance, reward, and dependence. As such, opioids are liable for addiction. Traditionally, opioid addiction was viewed as a solely neuronal process, and while substantial headway has been made into understanding the molecular and cellular mechanisms mediating this process, research has however, been relatively ambivalent to how the rest of the central nervous system (CNS) responds to opioids. Evidence over the past 20 years has clearly demonstrated the importance of the immunocompetent cells of the CNS (glia) in many aspects of opioid pharmacology. Particular focus has been placed on microglia and astrocytes, who in response to opioids, become activated and release inflammatory mediators. Importantly, the mechanism underlying immune activation is beginning to be elucidated. Evidence suggests an innate immune pattern-recognition receptor (toll-like receptor 4) as an integral component underlying opioid-induced glial activation. The subsequent proinflammatory response may be viewed akin to neurotransmission creating a process termed central immune signaling. Translationally, we are beginning to appreciate the importance of central immune signaling as it contributes to many behavioral actions of addiction including reward, withdrawal, and craving. As such, the aim of this chapter is to review and integrate the neuronal and central immune signaling perspective of addiction.

Trial registration: NCT00723177 NCT01740414.

Keywords: Addiction; Allostasis; Chemokine; Cytokine; Glia; Innate immune; Neurokine; Opioids; Toll-like receptor.

Publication types

  • Review

MeSH terms

  • Analgesics, Opioid / metabolism*
  • Analgesics, Opioid / pharmacology
  • Animals
  • Cytokines / metabolism
  • Humans
  • Immunity, Innate / drug effects
  • Immunity, Innate / physiology*
  • Microglia / drug effects
  • Opioid-Related Disorders / immunology*
  • Opioid-Related Disorders / pathology
  • Signal Transduction / drug effects
  • Toll-Like Receptor 4 / metabolism*


  • Analgesics, Opioid
  • Cytokines
  • Toll-Like Receptor 4

Associated data