GABA decreases in the spinal cord dorsal horn after peripheral neurectomy

doi:10.1016/0006-8993(93)90167-L

Brain Research

Volume 620, Issue 2, 27 August 1993, Pages 287-291

https://doi.org/10.1016/0006-8993(93)90167-L Get rights and content

Abstract

A significant fall in the number of GABA-immunoreactive cells in laminae I–III of the rat spinal cord occured in the somatotopic area of projection of the sciatic nerve after nerve transection. The decrease started at 2 weeks post-neurectomy, and at 4 weeks ipsilateral mean cell numbers were approximately 72% of contralateral control values. Similarly, the concentration of GABA in spinal homogenates was significantly reduced 4 weeks post-neurectomy. These data, together with our recent finding of an increase in spinal GABA during chronic inflammation of the hindlimb, suggest that the level of GABA in the dorsal horn is regulated by the amount of primary afferent input.

References (54)

AlbersR.W. et al.
The distribution of glutamic decarboxylase in the nervous system of the rhesus monkey
J. Biol. Chem.
(1959)
BarberR. et al.
GABAergic terminals are presynaptic to primary afferent terminals in the substantia gelatinosa of the rat spinal cord
Brain Res.
(1978)
BarbutD. et al.
Substance P in the spinal cord dorsal horn decreases following peripheral nerve injury
Brain Res.
(1981)
CoderreT.J. et al.
Deafferentation and chronic pain in animals: an evaluation of evidence suggesting autotomy is related to pain
Pain
(1986)
DeFeudisF.V.
Gamma-aminobutyric acid-ergic analgesia: implications for γ-aminobutyric acid-ergic therapy for drug addictions
Drug Alcohol Dependence
(1984)
DevorM. et al.
Mapping of acid phosphatase afferents in the rat dorsal horn
Brain Res.
(1980)
FitzgeraldM. et al.
Nerve growth factor counteracts the neurophysiological and neurochemical effects of chronic sciatic nerve section
Brain Res.
(1985)
GobelS. et al.
Degenerative changes in primary trigeminal axons and in neurons in nucleus caudalis following tooth pulp extirpations in the cat
Brain Res.
(1977)
HillR.C. et al.
Analgesic properties of the GABA-mimetic THIP
Eur. J. Pharmacol.
(1981)
HuntS.P. et al.
An immunohistochemical study of neuronal populations containing neuropeptides or γ-aminobutyrate withinhe superficial layers of the rat dorsal horn
Neuroscience
(1981)

KellyJ.S. et al.

Reduction of GAD I activity from the dorsal lateral region of deafferented rat spinal cord

Brain Res.

(1973)

MagoulR. et al.

Anatomical distribution and ultrastructural organization of the GABAergic system in the rat spinal cord. An immunocytochemical study using anti-GABA antibodies

Neuroscience

(1987)

MaxwellD.J. et al.

Relationships between hair-follicle afferent terminations and glutamic acid decarboxylase-containing boutons in the cat's spinal cord

Brain Res.

(1987)

MolanderC. et al.

Laminar distribution and somatotopic organization of primary afferent fibers from hindlimb nerves in the dorsal horn. A study by transganglionic transport of horseradish peroxidase in the rat

Neuroscience

(1986)

OttersenO.P. et al.

Localization of amino acid neurotransmitters by immunocytochemistry

Trends Neurosci.

(1987)

Ribeiro-da-SilvaA. et al.

Neuronal uptake of [³H]GABA and [³H] glycine in laminae I–III (substantia gelatinosa Rolandi) of the rat spinal cord. An autoradiographic study

Brain Res.

(1980)

SingerE. et al.

Reduction of [³H]muscimol binding sites in rat dorsal spinal cord after neonatal capsaicin treatment

Brain Res.

(1980)

SugimotoT. et al.

Transsynaptic degeneration in the superficial dorsal horn after sciatic nerve injury: effects of a chronic constriction injury, transection, and strychnine

Pain

(1990)

ToddA.J. et al.

GABA-immunoreactive neurons in the dorsal horn of the rat spinal cord

Neuroscience

(1989)

WallP.D. et al.

The effect of peripheral nerve injury on dorsal root potentials and on transmission of afferent signals into the spinal cord

Brain Res.

(1981)

WallP.D. et al.

The response of rat spinal cord cells to unmyelinated afferents after peripheral nerve section and after changes in the substance P levels

Neuroscience

(1981)

WallP.D. et al.

Ongoing activity in peripheral nerves. II. The physiology and pharmacology of impulses originating in a neurona

Exp. Neurol.

(1974)

WallP.D. et al.

Ongoing activity in peripheral nerve. III. Injury discharge

Exp. Neurol.

(1974)

AkhtarN.D. et al.

The effects of sensory deprivation on glutamic decarboxylase immunoreactivity in the rat SmI barrel cortex

Soc. Neurosci. Abstr.

(1987)

Castro-LopesJ.M. et al.

Ultrastructural changes of the central scalloped (C1) primary afferent endings of synaptic glomeruli in the substantia gelatinosa Rolando after peripheral neurotomy

J. Neurocytol.

(1990)

Castro-LopesJ.M. et al.

Increase in GABAergic cells and GABA levels in the spinal cord in unilateral cord in unilateral inflammation of the hindlimb in the rat

Eur. J. Neurosci.

(1992)

CsillikB. et al.

Transganglionic regulation by nerve growth factor of the primary nociceptive analyzer

Neurosci. Lett.

(1983)

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: Supported by Grant PMCT/C/SAU/49/90 from JNICT, and by INIC, Lisbon.

^*: The authors wish to thank the generous aid of Dr. Laura Vilarinho (Medical Genetics Institute, Oporto) for the biochemical analysis, and Prof. D. Moura (Department of Pharmacology, Faculty of Medicine of Oporto) for the radioactivity countings. We are grateful to Prof. P. McWilliam (Worsley Medical/Dental School, Leeds University) for careful reading of the manuscript, and Dr. T.R. Tölle (Max-Planck-Institut for Psychiatry, Munich) for helpful discussions.

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GABA decreases in the spinal cord dorsal horn after peripheral neurectomy

Abstract

J. Biol. Chem.

Brain Res.

Brain Res.

Pain

Drug Alcohol Dependence

Brain Res.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Neuroscience

Brain Res.

Neuroscience

Brain Res.

Neuroscience

Trends Neurosci.

Brain Res.

Brain Res.

Pain

Neuroscience

Brain Res.

Neuroscience

Exp. Neurol.

Exp. Neurol.

The effects of sensory deprivation on glutamic decarboxylase immunoreactivity in the rat SmI barrel cortex

Soc. Neurosci. Abstr.

Ultrastructural changes of the central scalloped (C1) primary afferent endings of synaptic glomeruli in the substantia gelatinosa Rolando after peripheral neurotomy

J. Neurocytol.

Increase in GABAergic cells and GABA levels in the spinal cord in unilateral cord in unilateral inflammation of the hindlimb in the rat

Eur. J. Neurosci.

Transganglionic regulation by nerve growth factor of the primary nociceptive analyzer

Neurosci. Lett.