Spinal Protein Kinase Mζ Regulates α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Trafficking and Dendritic Spine Plasticity via Kalirin-7 in the Pathogenesis of Remifentanil-induced Postincisional Hyperalgesia in Rats

Author:

Zhang Linlin1,Guo Suqian1,Zhao Qi1,Li Yize1,Song Chengcheng1,Wang Chunyan1,Yu Yonghao1,Wang Guolin1

Affiliation:

1. From the Tianjin Research Institute of Anesthesiology and Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.

Abstract

Abstract Background Intraoperative remifentanil anesthesia exaggerates postoperative pain sensitivity. Recent studies recapitulate the significance of protein kinase Mζ in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated pathologic pain. Kalirin-7, a Rho guanine nucleotide exchange factor, coordinates AMPA receptor trafficking and dendritic spine plasticity. This study examines whether protein kinase Mζ and Kalirin-7 contribute to remifentanil-induced postincisional hyperalgesia via AMPA receptor. Methods Plantar incision was performed 10 min after the start of remifentanil infusion (1 µg · kg−1 · min−1 for 60 min). Paw withdrawal threshold (primary outcome), spinal protein kinase Mζ activity, Kalirin-7 expression, AMPA receptor trafficking, and spine morphology were assessed. Protein kinase Mζ inhibitor and Kalirin-7 knockdown by short hairpin RNA elucidated the mechanism and prevention of hyperalgesia. Whole-cell patch-clamp recording analyzed the role of protein kinase Mζ in spinal AMPA receptor–induced current. Results Remifentanil reduced postincisional paw withdrawal threshold (mean ± SD, control vs. hyperalgesia, 18.9 ± 1.6 vs. 5.3 ± 1.2 g, n = 7) at postoperative 48 h, which was accompanied by an increase in spinal protein kinase Mζ phosphorylation (97.8 ± 25.1 vs. 181.5 ± 18.3%, n = 4), Kalirin-7 production (101.9 ± 29.1 vs. 371.2 ± 59.1%, n = 4), and number of spines/10 µm (2.0 ± 0.3 vs. 13.0 ± 1.6, n = 4). Protein kinase Mζ inhibitor reduced remifentanil-induced hyperalgesia, Kalirin-7 expression, and GluA1 trafficking. Incubation with protein kinase Mζ inhibitor reversed remifentanil-enhanced AMPA receptor-induced current in dorsal horn neurons. Kalirin-7 deficiency impaired remifentanil-caused hyperalgesia, postsynaptic GluA1 insertion, and spine plasticity. Selective GluA2-lacking AMPA receptor antagonist prevented hyperalgesia in a dose-dependent manner. Conclusions Spinal protein kinase Mζ regulation of GluA1-containing AMPA receptor trafficking and spine morphology via Kalirin-7 overexpression is a fundamental pathogenesis of remifentanil-induced hyperalgesia in rats.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Anesthesiology and Pain Medicine

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