Norepinephrine facilitates inhibitory transmission in substantia gelatinosa of adult rat spinal cord (part 1): effects on axon terminals of GABAergic and glycinergic neurons.
BACKGROUND
The activation of descending norepinephrine-containing fibers from the brain stem inhibits nociceptive transmission at the spinal level. How these descending noradrenergic pathways exert the analgesic effect is not understood fully. Membrane hyperpolarization of substantia gelatinosa (Rexed lamina II) neurons by the activation of alpha2 receptors may account for depression of pain transmission. In addition, it is possible that norepinephrine affects transmitter release in the substantia gelatinosa.


METHODS
Adult male Sprague-Dawley rats (9-10 weeks of age, 250-300 g) were used in this study. Transverse spinal cord slices were cut from the isolated lumbar cord. The blind whole-cell patch-clamp technique was used to record from neurons. The effects of norepinephrine on the frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents were evaluated.


RESULTS
In the majority of substantia gelatinosa neurons tested, norepinephrine (10-100 microM) dose-dependently increased the frequency of gamma-aminobutyric acid (GABA)ergic and glycinergic miniature inhibitory postsynaptic currents; miniature excitatory postsynaptic currents were unaffected. This augmentation was mimicked by an alpha1-receptor agonist, phenylephrine (10-60 microM), and inhibited by alpha1-receptor antagonists prazosin (0.5 microM) and 2-(2,6-dimethoxyphenoxyethyl) amino-methyl-1,4-benzodioxane (0.5 microM). Neither postsynaptic responsiveness to exogenously applied GABA and glycine nor the kinetics of GABAergic and glycinergic inhibitory postsynaptic currents were affected by norepinephrine.


CONCLUSIONS
These results suggest that norepinephrine enhances inhibitory synaptic transmission in the substantia gelatinosa through activation of presynaptic alpha1 receptors, thus providing a mechanism underlying the clinical use of alpha1 agonists with local anesthetics in spinal anesthesia.
Baba
H
H
Department of Anesthesiology, Niigata University School of Medicine, Japan. baba@helix.mgh.harvard.edu
Shimoji
K
K
Yoshimura
M
M
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005998:Glycine / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects*; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects*; D013376:Substantia Gelatinosa / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D018340:Receptors, Adrenergic, alpha-1; D005680:gamma-Aminobutyric Acid; D005998:Glycine; D009638:Norepinephrine