Bidirectional neuron-glia interactions triggered by deficiency of glutamate uptake at spinal sensory synapses.
Bidirectional interactions between neurons and glial cells are crucial to the genesis of pathological pain. The mechanisms regulating these interactions and the role of this process in relaying synaptic input in the spinal dorsal horn remain to be established. We studied the role of glutamate transporters in the regulation of such interactions. On pharmacological blockade of glutamate transporters, slow inward currents (SICs) appeared spontaneously and/or were evoked by peripheral synaptic input in the spinal superficial dorsal horn neurons, including the spinothalamic tract neurons. We showed that the SICs were induced by the release of glutamate from glial cells. On inhibition of glutamate uptake, the stimulation-induced, synaptically released glutamate activated glial cells and caused glial cells to release glutamate. Glial-derived glutamate acted on extrasynaptic N-methyl-d-aspartate (NMDA) receptors mainly composed of NR2B receptors and generated SICs, which led to depolarization and action potential generation in superficial spinal dorsal horn neurons. Thus glutamate transporters regulate glutamatergic neuron-glia interactions at spinal sensory synapses. When glutamate uptake is impaired, glial cells function like excitatory interneurons-they are activated by peripheral synaptic input and release glutamate to activate postsynaptic neurons in spinal pain pathways.
Nie
Hui
H
Department of Pain Medicine, Division of Anesthesiology and Critical Care, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Zhang
Haijun
H
Weng
Han-Rong
HR
D000596:Amino Acids; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001703:Biophysics; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009434:Neural Pathways / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; C120673:benzyloxyaspartate; C098463:dolaisoleucine; D001224:Aspartic Acid; D018698:Glutamic Acid