Peripheral inflammation activated focal adhesion kinase signaling in spinal dorsal horn of mice.

Abstract

Focal adhesion kinase (FAK) is one of the nonreceptor protein tyrosine kinases critical for the dynamic regulation of cell adhesion structures. Recent studies have demonstrated that FAK is also localized at excitatory glutamatergic synapses and is involved in long-term modification of synaptic strength. However, whether FAK is engaged in nociceptive processing in the spinal dorsal horn remains unresolved. The current study shows that intraplantar injection of complete Freund's adjuvant (CFA) in mice significantly increases FAK autophosphorylation at Tyr397, indicating a close correlation of FAK activation with inflammatory pain. FAK activation depended on the activity of N-methyl-D-aspartate-subtype glutamate receptor (NMDAR) and metabotropic glutamate receptor (mGluR) because pharmacological inhibition of NMDAR or group I mGluR totally abolished FAK phosphorylation induced by CFA. The active FAK operated to stimulate extracellular signal-regulated kinase1/2 (ERK1/2), which boosted the protein expression of GluN2B subunit-containing NMDAR at the synaptosomal membrane fraction. Inhibition of FAK activity by spinal expression of a kinase-dead FAK(Y397F) mutant repressed ERK1/2 hyperactivity and reduced the synaptic concentration of NMDAR in CFA-injected mice. Electrophysiological recording demonstrated that intracellular loading of specific anti-FAK antibody significantly reduced the amplitudes of NMDAR-mediated excitatory postsynaptic currents on lamina II neurons from inflamed mice but not from naive mice. Behavioral tests showed that spinal expression of FAK(Y397F) generated a long-lasting alleviation of CFA-induced mechanical allodynia and thermal hyperalgesia. These data indicate that FAK might exaggerate NMDAR-mediated synaptic transmission in the spinal dorsal horn to sensitize nociceptive behaviors.

• Authors: Xia Lian, Xin-Tai Wang, Wen-Tao Wang, Xian Yang, Zhan-Wei Suo, Xiao-Dong Hu
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 93 Issue 6 Pg. 873-81 (Jun 2015) ISSN: 1097-4547 [Electronic] United States
• PMID: 25612833 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Wiley Periodicals, Inc.

Chemical References

• Butadienes
• Enzyme Inhibitors
• Neurotransmitter Agents
• Nitriles
• Receptors, N-Methyl-D-Aspartate
• U 0126
• Freund's Adjuvant
• Focal Adhesion Kinase 1
• Ptk2 protein, mouse

Topics

• Animals
• Butadienes (pharmacology)
• Disease Models, Animal
• Enzyme Activation (drug effects, genetics)
• Enzyme Inhibitors (pharmacology)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Freund's Adjuvant (toxicity)
• MAP Kinase Signaling System (drug effects, genetics)
• Male
• Mice
• Mice, Inbred Strains
• Mutation (genetics)
• Neurons (drug effects, physiology)
• Neurotransmitter Agents (pharmacology)
• Nitriles (pharmacology)
• Patch-Clamp Techniques
• Peripheral Nervous System Diseases (chemically induced, genetics, pathology)
• Phosphorylation (drug effects, genetics)
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Signal Transduction (physiology)
• Spinal Cord Dorsal Horn (metabolism, pathology)
• Subcellular Fractions (metabolism, pathology)
• Synaptic Potentials (drug effects, genetics)
• Transduction, Genetic