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.

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 · min 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.

• Authors: Linlin Zhang, Suqian Guo, Qi Zhao, Yize Li, Chengcheng Song, Chunyan Wang, Yonghao Yu, Guolin Wang
• Journal: Anesthesiology (Anesthesiology) Vol. 129 Issue 1 Pg. 173-186 (07 2018) ISSN: 1528-1175 [Electronic] United States
• PMID: 29578864 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Guanine Nucleotide Exchange Factors
• Kalrn protein, rat
• Receptors, AMPA
• Protein Kinase C
• protein kinase M zeta, rat
• Remifentanil

Topics

• Analgesics, Opioid (toxicity)
• Animals
• Dendritic Spines (drug effects, metabolism)
• Guanine Nucleotide Exchange Factors (biosynthesis)
• Hyperalgesia (chemically induced, metabolism)
• Male
• Neuronal Plasticity (drug effects, physiology)
• Organ Culture Techniques
• Pain, Postoperative (chemically induced, metabolism)
• Protein Kinase C (physiology)
• Protein Transport (drug effects, physiology)
• Rats
• Rats, Sprague-Dawley
• Receptors, AMPA (metabolism)
• Remifentanil (toxicity)
• Surgical Wound (complications, metabolism)