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

Ming Chun Hsieh, Cheng Yuan Lai, Chou Ming Yeh, Po Sheng Yang, Jen Kun Cheng, Hsueh Hsiao Wang, Kuan Hung Lin, Siao Tong Nie, Tzer Bin Lin, Hsien Yu Peng

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2 Citations (Scopus)

Abstract

Background: Nonsense-mediated messenger RNA (mRNA) decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. The authors 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 (UPF1) expression in the dorsal horn (mean ± SD; 0.34 ± 0.19 in the sham ipsilateral group vs. 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 vs. 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 (eIF4A3) triggered SMG1 kinase (0.06 ± 0.02 in the sham group vs. 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 vs. 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. Pharmacologic or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors after spinal nerve ligation. conclusions: This study suggests that phosphorylated UPF1–dependent nonsense-mediated μ-opioid receptor mRNA decay is involved in the pathogenesis of neuropathic pain.

Original languageEnglish
Pages (from-to)634-655
Number of pages22
JournalAnesthesiology
Volume138
Issue number6
DOIs
Publication statusPublished - Jun 1 2023

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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