Inflammatory mediators of opioid tolerance: Implications for dependency and addiction

Peptides. 2019 May:115:51-58. doi: 10.1016/j.peptides.2019.01.003. Epub 2019 Mar 16.

Abstract

Each year, over 50 million Americans suffer from persistent pain, including debilitating headaches, joint pain, and severe back pain. Although morphine is amongst the most effective analgesics available for the management of severe pain, prolonged morphine treatment results in decreased analgesic efficacy (i.e., tolerance). Despite significant headway in the field, the mechanisms underlying the development of morphine tolerance are not well understood. The midbrain ventrolateral periaqueductal gray (vlPAG) is a primary neural substrate for the analgesic effects of morphine, as well as for the development of morphine tolerance. A growing body of literature indicates that activated glia (i.e., microglia and astrocytes) facilitate pain transmission and oppose morphine analgesia, making these cells important potential targets in the treatment of chronic pain. Morphine affects glia by binding to the innate immune receptor toll-like receptor 4 (TLR4), leading to the release of proinflammatory cytokines and opposition of morphine analgesia. Despite the established role of the vlPAG as an integral locus for the development of morphine tolerance, most studies have examined the role of glia activation within the spinal cord. Additionally, the role of TLR4 in the development of tolerance has not been elucidated. This review attempts to summarize what is known regarding the role of vlPAG glia and TLR4 in the development of morphine tolerance. These data, together, provide information about the mechanism by which central nervous system glia regulate morphine tolerance, and identify a potential therapeutic target for the enhancement of analgesic efficacy in the clinical treatment of chronic pain.

Keywords: Glia; Opioid; Periaqueductal gray; Tolerance; Toll-like receptor 4; Tumor necrosis factor.

Publication types

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

MeSH terms

  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / therapeutic use
  • Chronic Pain / drug therapy*
  • Chronic Pain / metabolism
  • Drug Tolerance*
  • Humans
  • Inflammation Mediators / metabolism*
  • Morphine / adverse effects*
  • Morphine / therapeutic use
  • Opioid-Related Disorders / metabolism*
  • Periaqueductal Gray / metabolism
  • Spinal Cord / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

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