14-3-3γ mediates the long-term inhibition of peripheral kappa opioid receptor antinociceptive signaling by norbinaltorphimine

Michael J. Wedemeyer, Elaine M. Jennings, Hudson R. Smith, Teresa S. Chavera, Raehannah J. Jamshidi, Kelly A. Berg, William P. Clarke

Research output: Contribution to journalArticlepeer-review

Abstract

Long-term inhibition of kappa opioid receptor (KOR) signaling in peripheral pain-sensing neurons is a potential obstacle for development of peripherally-restricted KOR agonists that produce analgesia. Such a long-term inhibitory mechanism is invoked from activation of c-Jun N-terminal kinase (JNK) that follows a single injection of the KOR antagonist norbinaltorphimine (norBNI). This effect requires protein synthesis of an unknown mediator in peripheral pain-sensing neurons. Using 2D difference gel electrophoresis with tandem mass spectrometry, we have identified that the scaffolding protein 14-3-3γ is upregulated in peripheral sensory neurons following activation of JNK with norBNI. Knockdown of 14-3-3γ by siRNA eliminates the long-term reduction in KOR-mediated cAMP signaling by norBNI in peripheral sensory neurons in culture. Similarly, knockdown of 14-3-3γ in the rat hind paw abolished the norBNI-mediated long-term reduction in peripheral KOR-mediated antinociception. Further, overexpression of 14-3-3γ in KOR expressing CHO cells prevented KOR-mediated inhibition of cAMP signaling. These long-term effects are selective for KOR as heterologous regulation of other receptor systems was not observed. These data suggest that 14-3-3γ is both necessary and sufficient for the long-term inhibition of KOR by norBNI in peripheral sensory neurons.

Original languageEnglish (US)
Article number109251
JournalNeuropharmacology
Volume220
DOIs
StatePublished - Dec 1 2022

Keywords

  • 14-3-3γ
  • Kappa opioid receptor
  • Norbinaltorphimine
  • Opioids
  • Pain
  • Sensory neurons

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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