The contribution of the descending pain modulatory pathway in opioid tolerance

Lindsay M. Lueptow, Amanda K. Fakira, Erin N. Bobeck

Research output: Contribution to journalReview articlepeer-review

38 Scopus citations


Opioids remain among the most effective pain-relieving therapeutics. However, their long-term use is limited due to the development of tolerance and potential for addiction. For many years, researchers have explored the underlying mechanisms that lead to this decreased effectiveness of opioids after repeated use, and numerous theories have been proposed to explain these changes. The most widely studied theories involve alterations in receptor trafficking and intracellular signaling. Other possible mechanisms include the recruitment of new structural neuronal and microglia networks. While many of these theories have been developed using molecular and cellular techniques, more recent behavioral data also supports these findings. In this review, we focus on the mechanisms that underlie tolerance within the descending pain modulatory pathway, including alterations in intracellular signaling, neural-glial interactions, and neurotransmission following opioid exposure. Developing a better understanding of the relationship between these various mechanisms, within different parts of this pathway, is vital for the identification of more efficacious, novel therapeutics to treat chronic pain.

Original languageEnglish
Article number886
JournalFrontiers in Neuroscience
Issue numberNOV
StatePublished - 27 Nov 2018


  • Dorsal horn
  • Opioid
  • Periaqueductal gray (PAG)
  • RVM
  • Tolerance


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