Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism

&NA; Neuropathic pain may be effectively relieved by electric stimulation of the spinal cord (SCS). However, the underlying mechanisms for the ensuing pain relief are poorly understood. In a rat model of neuropathy displaying hypersensitivity to innocuous tactile stimuli, (allodynia), we have earlier demonstrated that SCS may normalise withdrawal response thresholds. In the present study, using microdialysis, it is shown that SCS induces a decreased release of the dorsal horn excitatory amino acids (EAA), glutamate and aspartate, concomitant with an increase of the GABA release. Local perfusion with a GABAB‐receptor antagonist in the dorsal horn transiently abolishes the SCS‐induced suppression of the EAA release. Thus, the effect of SCS on neuropathic pain and allodynia may be due to an activation of local GABAergic mechanisms inhibiting the EAA release which is chronically elevated in such conditions.

[1]  M. Raiteri,et al.  Studies on [3H]GABA and endogenous GABA release in rat cerebral cortex suggest the presence of autoreceptors of the GABAB type. , 1987, European journal of pharmacology.

[2]  G. Collingridge,et al.  CGP 55845A: A potent antagonist of GABAb receptors in the CA1 region of rat hippocampus , 1993, Neuropharmacology.

[3]  T. Yaksh,et al.  Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. , 1994, The Journal of pharmacology and experimental therapeutics.

[4]  Y. Hori,et al.  Effects of iontophoretically released amino acids and amines on primate spinothalamic tract cells , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  N. Bowery,et al.  GABAA and GABAB receptor site distribution in the rat central nervous system , 1987, Neuroscience.

[6]  B. Meyerson,et al.  Spinal cord stimulation in animal models of mononeuropathy: effects on the withdrawal response and the flexor reflex , 1995, Pain.

[7]  N. Bowery.  GABAB receptor pharmacology. , 1993, Annual review of pharmacology and toxicology.

[8]  G. Wilcox,et al.  Phencyclidine selectively blocks a spinal action of N-methyl-d-aspartate in mice , 1986, Neuroscience Letters.

[9]  P F Morrison,et al.  Effects of Different Semipermeable Membranes on In Vitro and In Vivo Performance of Microdialysis Probes , 1990, Journal of neurochemistry.

[10]  Ronald Dubner,et al.  A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury , 1990, Pain.

[11]  K. Paik,et al.  N-Methyl-d-aspartate (NMDA) and non-NMDA glutamate receptor antagonists differentially suppress dorsal horn neuron responses to mechanical stimuli in rats with peripheral nerve injury , 1996, Neuroscience Letters.

[12]  M. Randić,et al.  Actions of (−)-baclofen on rat dorsal horn neurons , 1991, Brain Research.

[13]  R. Melzack,et al.  The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  N. Dun,et al.  Presynaptic GABAB receptor activation attenuates synaptic transmission to rat sympathetic preganglionic neurons in vitro , 1992, Brain Research.

[15]  G. Volsi,et al.  Glutamate immunocytochemistry in the dorsal horn after injury or stimulation of the sciatic nerve of rats , 1993, Brain Research Bulletin.

[16]  Bengt Linderoth,et al.  Effects of spinal cord stimulation on touch-evoked allodynia involve GABAergic mechanisms. An experimental study in the mononeuropathic rat , 1996, PAIN®.

[17]  S. Harrison,et al.  Pre treatment with MK-801, a non-competitive NMDA antagonist, prevents development of mechanical hyperalgesia in a rat model of chronic neuropathy, but not in a model of chronic inflammation , 1994, Neuroscience Letters.

[18]  T. Yaksh,et al.  Analysis of Drug Interaction between Intrathecal Clonidine and MK‐801 in Peripheral Neuropathic Pain Rat Model , 1995, Anesthesiology.

[19]  B. Meyerson,et al.  Dorsal column stimulation: modulation of somatosensory and autonomic function , 1995 .

[20]  T. Doubell,et al.  The pathophysiology of chronic pain — increased sensitivity to low threshold Aβ-fibre inputs , 1994, Current Opinion in Neurobiology.

[21]  Gary J. Bennett,et al.  A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man , 1988, Pain.

[22]  N. Bowery,et al.  GABA and its receptors in the spinal cord. , 1996, Trends in pharmacological sciences.

[23]  U. Ungerstedt,et al.  Gamma-aminobutyric acid is released in the dorsal horn by electrical spinal cord stimulation: an in vivo microdialysis study in the rat. , 1994, Neurosurgery.

[24]  U. Ungerstedt,et al.  On the Origin of Extracellular Glutamate Levels Monitored in the Basal Ganglia of the Rat by In Vivo Microdialysis , 1996, Journal of neurochemistry.

[25]  Patrick D. Wall,et al.  Central hyperexcitability triggered by noxious inputs , 1993, Current Opinion in Neurobiology.

[26]  G. Wilcox,et al.  Nociceptive action of excitatory amino acids in the mouse: effects of spinally administered opioids, phencyclidine and sigma agonists. , 1987, The Journal of pharmacology and experimental therapeutics.

[27]  P. Waldmeier,et al.  GABA and glutamate release affected by GABAB receptor antagonists with similar potency: no evidence for pharmacologically different presynaptic receptors , 1994, British journal of pharmacology.

[28]  R. North,et al.  Baclofen and adenosine inhibit synaptic potentials mediated by gamma-aminobutyric acid and glutamate release in rat nucleus accumbens. , 1991, The Journal of pharmacology and experimental therapeutics.

[29]  D. Sah,et al.  Neurotransmitter modulation of calcium current in rat spinal cord neurons , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[30]  I. Tavares,et al.  GABA decreases in the spinal cord dorsal horn after peripheral neurectomy , 1993, Brain Research.

[31]  W T O'Connor,et al.  An animal model for the study of brain transmittor release in response to spinal cord stimulation in the awake, freely moving rat: preliminary results from the periaqueductal grey matter. , 1993, Acta neurochirurgica. Supplementum.

[32]  D. Price,et al.  Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy , 1992, Brain Research.

[33]  F. P. Haugen.  Pain mechanisms. , 1967, Caementum.

[34]  D. Tracey,et al.  Aspartate-like immunoreactivity in primary afferent neurons , 1991, Neuroscience.

[35]  K. McCarthy,et al.  Glutamate blocks astroglial stellation: Effect of glutamate uptake and volume changes , 1994, Glia.