Specific involvement in neuropathic pain of AMPA receptors and adapter proteins for the GluR2 subunit.
Chronic pain states arise from peripheral nerve injury and are inadequately treated with current analgesics. Using intrathecal drug administration in a rat model of neuropathic pain, we demonstrate that AMPA receptors play a role in the central sensitisation that is thought to underpin chronic pain. The GluR2 subunit of the AMPA receptor binds to a number of intracellular adapter proteins including GRIP, PICK1 and NSF, which may link the receptor to proteins with signalling, scaffolding and other roles. We implicate for the first time a possible role for GRIP, PICK1 and NSF in neuropathic sensitisation from experiments with cell-permeable blocking peptides mimicking their GluR2 interaction motifs and also demonstrate differential changes in expression of these proteins following peripheral nerve injury. These studies suggest a critical involvement of protein:protein complexes associated with the AMPA receptor in neuropathic pain, and the possibility that they may have potential as novel therapeutic targets.
Garry
Emer M
EM
Centre for Neuroscience Research, Division of Preclinical Veterinary Sciences, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Summerhall, Edinburgh EH9 1QH, Scotland, UK.
Moss
Andrew
A
Rosie
Roberta
R
Delaney
Ada
A
Mitchell
Rory
R
Fleetwood-Walker
Susan M
SM
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002908:Chronic Disease; D003598:Cytoskeletal Proteins; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D052066:N-Ethylmaleimide-Sensitive Proteins; D009437:Neuralgia / Q000378:metabolism* / Q000503:physiopathology; D009687:Nuclear Proteins; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D010523:Peripheral Nervous System Diseases / Q000378:metabolism* / Q000503:physiopathology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D033921:Vesicular Transport Proteins; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018691:Excitatory Amino Acid Antagonists; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D010455:Peptides; D021122:Protein Subunits; D012333:RNA, Messenger; D018091:Receptors, AMPA; D011993:Recombinant Fusion Proteins; D033921:Vesicular Transport Proteins; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D052066:N-Ethylmaleimide-Sensitive Proteins; C498733:Nsf protein, mouse; C498737:Nsf protein, rat; C104722:glutamate receptor ionotropic, AMPA 2