Activation of TREK-1 by morphine results in analgesia without adverse side effects

Nat Commun. 2013;4:2941. doi: 10.1038/ncomms3941.

Abstract

Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same μ opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from μ opioid receptor. We demonstrate that the TREK-1 K(+) channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K(+) channel, acting downstream from the μ opioid receptor, might have strong analgesic effects without opioid-like adverse effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesia / methods*
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / therapeutic use
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Constipation
  • Crosses, Genetic
  • Dose-Response Relationship, Drug
  • Drug Tolerance
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Morphine / adverse effects*
  • Morphine / therapeutic use*
  • Naloxone / chemistry
  • Pain / drug therapy
  • Pain Management
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Receptors, Opioid, mu / metabolism
  • Respiratory Insufficiency
  • Signal Transduction
  • Time Factors

Substances

  • Analgesics, Opioid
  • Potassium Channels, Tandem Pore Domain
  • Receptors, Opioid, mu
  • potassium channel protein TREK-1
  • Naloxone
  • Morphine