Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Chronic Disease
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Cytoskeletal Proteins
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Excitatory Amino Acid Antagonists / pharmacology
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Functional Laterality / drug effects
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Functional Laterality / physiology
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Glutamic Acid / metabolism
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Hyperalgesia / drug therapy
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Hyperalgesia / metabolism
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Hyperalgesia / physiopathology
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Male
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N-Ethylmaleimide-Sensitive Proteins
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Neuralgia / metabolism*
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Neuralgia / physiopathology
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Nuclear Proteins*
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Pain Threshold / drug effects
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Pain Threshold / physiology
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Peptides / pharmacology
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Peripheral Nervous System Diseases / metabolism*
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Peripheral Nervous System Diseases / physiopathology
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Protein Binding / drug effects
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Protein Binding / physiology
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Protein Transport / drug effects
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Protein Transport / physiology
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Rats
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Rats, Wistar
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Receptors, AMPA / antagonists & inhibitors
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Receptors, AMPA / genetics
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Receptors, AMPA / metabolism*
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Recombinant Fusion Proteins / metabolism*
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Reflex / drug effects
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Reflex / physiology
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology
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Vesicular Transport Proteins*
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
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Carrier Proteins
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Cytoskeletal Proteins
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Excitatory Amino Acid Antagonists
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Nuclear Proteins
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PICK1 protein, rat
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Peptides
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Protein Subunits
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RNA, Messenger
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Receptors, AMPA
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Recombinant Fusion Proteins
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Vesicular Transport Proteins
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Glutamic Acid
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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N-Ethylmaleimide-Sensitive Proteins
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Nsf protein, mouse
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Nsf protein, rat
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glutamate receptor ionotropic, AMPA 2