New role for spinal Stargazin in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated pain sensitization after inflammation.
Considerable evidence has demonstrated that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blockade has an antinociceptive effect on inflammatory pain. Stargazin (STG) is the first transmembrane protein known to associate with AMPA receptors and regulate their synaptic targeting. However, it is not known whether STG is involved in inflammatory pain processing by regulating AMPA receptor function. In the present study, we investigated the effect of knockdown of spinal STG on AMPA receptor-mediated pain sensitization after inflammation. Antisense technology was employed to knock down STG expression in the spinal cord. We show that STG was expressed and interacted with AMPA receptor subunit GluR2 in the spinal cord. Intrathecally injected STG antisense oligodeoxyribonucleotide (ODN) specifically decreased STG expression in the lumbar spinal cord and dose dependently inhibited formalin-induced inflammatory pain in the second phase. More important was our finding for the first time that this specific STG antisense ODN diminished AMPA (0.1 mug)-enhanced formalin pain and lost its effect if pretreated with AMPA receptor antagonist CNQX. Our results demonstrate a new role for STG in central sensitization of inflammatory pain by interacting with AMPA receptors in the spinal cord.
Tao
Feng
F
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Skinner
John
J
Su
Qingning
Q
Johns
Roger A
RA
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D047468:Immunoprecipitation / Q000379:methods; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage; D010146:Pain / Q000209:etiology / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
C491911:Cacng2 protein, rat; D015220:Calcium Channels; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016376:Oligonucleotides, Antisense; D018091:Receptors, AMPA; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid