title: Glutamate transporters prevent excessive activation of NMDA receptors and extrasynaptic glutamate spillover in the spinal dorsal horn.
abstract: Activation of N-methyl-d-aspartate (NMDA) receptors in the spinal dorsal horn neurons is a key process related to sensory transmission, neural plasticity, and pathogenesis of pain. In this study, we investigated how activation of NMDA receptors in spinal substantia gelatinosa neurons is regulated by glutamate re-uptake through glutamate transporters located in the astrocytic and neuronal plasma membranes. Using visualized whole cell patch recording techniques, NMDA excitatory postsynaptic currents evoked by graded peripheral inputs in spinal substantia gelatinosa neurons of spinal slices from young adult rats were analyzed before and after combined inhibition of glial and neuronal glutamate transporters by d-threo-beta-benzyloxyaspartate (TBOA). Blockade of glutamate transporters increased the number and duration of NMDA receptors activated by weak and by strong primary afferent inputs as well as by exogenous glutamate. The enhancement in activation of NMDA receptors induced by TBOA was greater in neurons that have weaker synaptic input at baseline. Impaired glutamate uptake increased the open probability of NMDA channels and caused glutamate spillover outside the active synapses, leading to activation of extrasynaptic NMDA receptors and/or receptors located in neighboring synapses. Finally, blockade of glutamate transporters resulted in an increased proportion of NR2B subunit activation induced by peripheral input, and this increase was further augmented by stronger afferent input. These data indicate that glutamate transporters regulate spatiotemporal and intensity coding for sensory input and prevent excessive activation of glutamate receptors in the spinal dorsal horn. It is suggested that remedying dysfunctional glutamate transporters may be a potential new avenue to prevent the pathogenesis of pain.
authors.affiliation: Dept. of Anesthesiology and Pain Medicine, Div. of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, 1400 Holcombe Blvd., Unit 409, Houston, TX 77030-4009, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Nie
authors.forename: Han-Rong
authors.initials: HR
authors.lastname: Weng
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D018408:Patch-Clamp Techniques / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*
chemical_list: D027322:Amino Acid Transport System X-AG; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D018698:Glutamic Acid; D001640:Bicuculline