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14-3-3γ mediates the long-term inhibition of peripheral kappa opioid receptor antinociceptive signaling by norbinaltorphimine.
- Source :
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Neuropharmacology [Neuropharmacology] 2022 Dec 01; Vol. 220, pp. 109251. Date of Electronic Publication: 2022 Sep 17. - Publication Year :
- 2022
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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.<br />Competing Interests: Conflicts of interest Authors report no conflict of interest.<br /> (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 220
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 36126728
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2022.109251