title: Loss of Ca(2+)-permeable AMPA receptors in synapses of tonic firing substantia gelatinosa neurons in the chronic constriction injury model of neuropathic pain.
abstract: Synapses transmitting nociceptive information in the spinal dorsal horn undergo enduring changes following peripheral nerve injury. Indeed, such injury alters the expression of the GluA2 subunit of glutamatergic AMPA receptors (AMPARs) in the substantia gelatinosa and this predicts altered channel conductance and calcium permeability, leading to an altered function of excitatory synapses. We therefore investigated the functional properties of synaptic AMPA receptors in rat substantia gelatinosa neurons following 10-20d chronic constriction injury (CCI) of the sciatic nerve; a model of neuropathic pain. We measured their single-channel conductance and sensitivity to a blocker of calcium permeable AMPA receptors (CP-AMPARs), IEM1460 (50μM). In putative inhibitory, tonic firing neurons, CCI reduced the average single-channel conductance of synaptic AMPAR from 14.4±3.5pS (n=12) to 9.2±1.0pS (n=10, p<0.05). IEM1460 also more effectively antagonized evoked, spontaneous and miniature EPSCs in tonic neurons from sham operated animals than in those from animals that had been subjected to CCI. By contrast, CCI did not change the effectiveness of IEM1460 in delay firing neurons although average single channel conductance was increased from 7.6±1.2pS (n=11) to 12.2±1.5pS (n=10, p<0.01). CCI thus elicits plastic changes in a specific set of glutamatergic synapses of substantia gelatinosa due to subunit recomposition and loss of GluA2-lacking CP-AMPAR. These insights reveal a molecular mechanism of nerve injury acting at synapses of inhibitory neurons to reduce their drive and therefore inhibitory tone in the spinal cord, therefore contributing to the central sensitization associated with neuropathic pain.
authors.affiliation: Department of Pharmacology and Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2H7, Canada.
authors.forename: Yishen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biochemistry, School of Medicine, University of Washington, Seattle, WA 98195-7350, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7350, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Derkach
authors.affiliation: Department of Pharmacology and Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB T6G 2H7, Canada. Electronic address: peter.a.smith@ualberta.ca.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Smith
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003251:Constriction, Pathologic / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009437:Neuralgia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013376:Substantia Gelatinosa / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C110702:IEM 1460; D018091:Receptors, AMPA; D000218:Adamantane; D002118:Calcium
keywords: AMPA receptors; Chronic constriction injury; GluA2; IEM 1460; Neuropathic pain; Non-stationary fluctuation analysis; Release probability; Substantia gelatinosa; Synaptic plasticity