2. Academic Validation
  3. Phosphorylated upstream frameshift 1-dependent nonsense-mediated μ opioid receptor mRNA decay in the spinal cord contributes to the development of neuropathic allodynia-like behavior in rats

Phosphorylated upstream frameshift 1-dependent nonsense-mediated μ opioid receptor mRNA decay in the spinal cord contributes to the development of neuropathic allodynia-like behavior in rats

  • Anesthesiology. 2023 Mar 3. doi: 10.1097/ALN.0000000000004550.
Ming-Chun Hsieh 1,  Cheng-Yuan Lai 2,  Chou-Ming Yeh 3 4,  Po-Sheng Yang 1 5,  Jen-Kun Cheng 1 6,  Hsueh-Hsiao Wang 1,  Kuan-Hung Lin 1,  Siao-Tong Nie 1,  Tzer-Bin Lin 7 8 9,  Hsien-Yu Peng 1 2
Affiliations

Affiliations

  • 1 Department of Medicine, Mackay Medical College, New Taipei, Taiwan.
  • 2 Institute of Biomedical Sciences, MacKay Medical College, New Taipei City, Taiwan.
  • 3 Division of Thoracic Surgery, Department of Health, Taichung Hospital, Executive Yuan, Taichung, Taiwan.
  • 4 Central Taiwan University of Science and Technology, Taichung, Taiwan.
  • 5 Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan.
  • 6 Department of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan.
  • 7 Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei City, Taiwan.
  • 8 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.
  • 9 Institute of New Drug Development, College of Medicine, China Medical University, Taichung 40604, Taiwan.
PMID: 36867667 DOI: 10.1097/ALN.0000000000004550
Abstract

Background: Nonsense-mediated mRNA decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. We hypothesized that nonsense-mediated μ Opioid Receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia-like behavior in rats.

Methods: Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia-like behavior. The mRNA and protein expression contents in the dorsal horn of Animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by the von Frey test and the burrow test.

Results: On Day 7, spinal nerve ligation significantly increased phosphorylated upstream frameshift 1 (pUPF1) expression in the dorsal horn (0.34 ± 0.19 in the sham ipsilateral group versus 0.88 ± 0.15 in the nerve ligation ipsilateral group, p < 0.001, data in arbitrary units) and drove allodynia-like behaviors in rats (10.58 ± 1.72 g in the sham ipsilateral group versus 1.19 ± 0.31 g in the nerve ligation ipsilateral group, p < 0.001). No sex-based differences were found in either Western blotting or behavior tests in rats. Eukaryotic translation initiation factor 4A3 triggered SMG1 kinase (0.06 ± 0.02 in the sham group versus 0.20 ± 0.08 in the nerve ligation group, p = 0.005, data in arbitrary units)-mediated UPF1 phosphorylation, leading to increased nonsense-mediated mRNA decay factor SMG7 binding and µ-opioid receptor mRNA degradation (0.87 ± 0.11 fold in the sham group versus 0.50 ± 0.11 fold in the nerve ligation group, p = 0.002) in the dorsal horn of the spinal cord after spinal nerve ligation. Pharmacological or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors following spinal nerve ligation.

Conclusions: Our study suggests that phosphorylated upstream frameshift 1-dependent nonsense-mediated μ Opioid Receptor mRNA decay is involved in the pathogenesis of neuropathic pain.

Keywords

allodynia-like behaviors; mRNA decay; pUPF1; spinal; µ-opioid receptor.

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