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 alpha(2) 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 mu M) 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 alpha(1)-receptor agonist, phenylephrine (10-60 mu M), and inhibited by alpha(1)-receptor antagonists prazosin (0.5 mu M) and 2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane (0.5 mu M). Neither postsynaptic responsiveness to exogenously applied GABA and glycine nor the kinetics of GABAergic and glycinergic inhibitory postsynaptic currents were affected by norepinephrine. Conclusion: These results suggest that norepinephrine enhances inhibitory synaptic transmission in the substantia gelatinosa through activation of presynaptic alpha(1) receptors, thus providing a mechanism underlying the clinical use of of, agonists with local anesthetics in spinal anesthesia.