title: Peripheral nerve injury produces a sustained shift in the balance between glutamate release and uptake in the dorsal horn of the spinal cord.
abstract: Peripheral nerve injury provokes heightened excitability of primary sensory afferents including nociceptors, and elicits ectopic activity in lesioned and neighboring intact nerve fibers. The major transmitter released by sensory afferents in the superficial dorsal horn of the spinal cord is glutamate. Glutamate is critically involved in nociceptive signaling and the development of neuropathic pain. We recorded miniature excitatory postsynaptic currents (mEPSCs) from neurons in lamina II of the rat dorsal horn to assess spontaneous synaptic activity after spared nerve injury (SNI), a model of chronic neuropathic pain. Following SNI, the frequency of mEPSCs doubled, indicating heightened glutamate release from primary afferents or spinal interneurons. Consistent with this finding, glutamate concentrations in the cerebrospinal fluid were elevated at 1 and 4 weeks after SNI. Transmitter uptake was insufficient to prevent the rise in extracellular glutamate as the expression of glutamate transporters remained unchanged or decreased. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride, an antagonist of metabotropic glutamate receptor 5 (mGluR5), reduced the frequency of mEPSCs to its preinjury level, suggesting a positive feedback mechanism that involves facilitation of transmitter release by mGluR5 activation in the presence of high extracellular glutamate. Treatment with the β-lactam antibiotic ceftriaxone increased the expression of glutamate transporter 1 (Glt1) in the dorsal horn after SNI, raised transmitter uptake, and lowered extracellular glutamate. Improving glutamate clearance prevented the facilitation of transmitter release by mGluR5 and attenuated neuropathic pain-like behavior. Balancing glutamate release and uptake after nerve injury should be an important target in the management of chronic neuropathic pain.
authors.affiliation: F.M. Kirby Neurobiology Center, Children's Hospital and Harvard Medical School, Boston, MA, USA CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 6097, Valbonne, France Université de Nice-Sophia Antipolos, UMR 6097, Valbonne, France Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Goethe University, Frankfurt, Germany Departments of Anesthesiology and Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Perrine
authors.initials: P
authors.lastname: Inquimbert
authors.forename: Karsten
authors.initials: K
authors.lastname: Bartels
authors.forename: Olusegun B
authors.initials: OB
authors.lastname: Babaniyi
authors.forename: Lee B
authors.initials: LB
authors.lastname: Barrett
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
authors.forename: Joachim
authors.initials: J
authors.lastname: Scholz
mesh_terms: D000818:Animals; D059350:Chronic Pain / Q000209:etiology / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000209:etiology / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D059348:Peripheral Nerve Injuries / Q000150:complications / Q000378:metabolism*; D020671:Posterior Horn Cells / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018377:Neurotransmitter Agents; D018698:Glutamic Acid