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. 2009 Feb 18;158(4):1616-24.
doi: 10.1016/j.neuroscience.2008.11.022. Epub 2008 Nov 21.

Stimulation of alpha(1)-adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABA(A) receptors and T-type Ca(2+) channels

W-X Yuan  1 , S-R Chen, H Chen, H-L Pan
Affiliations

Stimulation of alpha(1)-adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABA(A) receptors and T-type Ca(2+) channels

W-X Yuan et al. Neuroscience. .

Abstract

Activation of the descending noradrenergic system inhibits nociceptive transmission in the spinal cord. Although both alpha(1)- and alpha(2)-adrenoceptors in the spinal cord are involved in the modulation of nociceptive transmission, it is not clear how alpha(1)-adrenoceptors regulate excitatory and inhibitory synaptic transmission at the spinal level. In this study, inhibitory and excitatory postsynaptic currents (IPSCs and EPSCs, respectively) were recorded from lamina II neurons in rat spinal cord slices. The specific alpha(1)-adrenoceptor agonist phenylephrine significantly increased the frequency of GABAergic spontaneous IPSCs in a concentration dependent manner, and this effect was abolished by the alpha(1)-adrenoceptor antagonist 2-(2,6-dimethoxyphenoxy)ethylaminomethyl-1,4-benzodioxane (WB4101). Phenylephrine also significantly reduced the amplitude of monosynaptic and polysynaptic EPSCs evoked from primary afferents. The inhibitory effect of phenylephrine on evoked monosynaptic glutamatergic EPSCs was largely blocked by the GABA(A) receptor antagonist picrotoxin and, to a lesser extent, by the GABA(B) receptor antagonist CGP55845. Furthermore, blocking T-type Ca(2+) channels with amiloride or mibefradil diminished the inhibitory effect produced by phenylephrine or the GABA(A) receptor agonist muscimol on monosynaptic EPSCs evoked from primary afferents. Collectively, these findings suggest that activation of alpha(1)-adrenoceptors in the spinal cord increases synaptic GABA release, which attenuates glutamatergic input from primary afferents mainly through GABA(A) receptors and T-type Ca(2+) channels. This mechanism of presynaptic inhibition in the spinal cord may be involved in the regulation of nociception by the descending noradrenergic system.

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Figures

Fig. 1
Fig. 1
Effect of phenylephrine on GABAergic sIPSCs of lamina II neurons. A, original traces of sIPSCs during control, application of 10, 25, 50, and 100 μM phenylephrine and washout in one lamina II neuron. B, cumulative probability plots of the same neuron in A show the distribution of inter-event interval and amplitude of sIPSCs during control and perfusion of 25 and 50 μM phenylephrine. C, summary data show the effect of phenylephrine on the frequency and amplitude of sIPSCs (n = 23 cells). Data are presented as means ± S.E.M. *, P < 0.05 compared with the baseline control. Phl, phenylephrine.
Fig. 2
Fig. 2
Effect of phenylephrine on GABAergic sIPSCs in lamina II neurons before and after WB4101 application. A, original traces of sIPSCs during control and application of 50 μM phenylephrine with and without 0.5 μM WB4101 in one lamina II neuron. B, cumulative probability plots of the same neuron in A show the distribution of inter-event interval and amplitude of sIPSCs during control and application of phenylephrine and phenylephrine plus WB4101. C, summary data show that 0.5 μM WB4101 abolished the effect of 50 μM phenylephrine on the frequency of sIPSCs (n = 9). D, group data show the reproducible effect of 50 μM phenylephrine on the frequency of sIPSCs (n = 8). Data presented as means ± S.E.M. *, P < 0.05 compared with the baseline control. Phl, phenylephrine; WB, WB4101.
Fig. 3
Fig. 3
Effect of phenylephrine on glutamatergic eEPSCs of lamina II neurons elicited from primary afferents. A, original traces of eEPSCs show identification of monosynaptic (left) and polysynaptic (right) eEPSCs in two separate lamina II neurons evoked by electrical stimulation of the dorsal root entry zone (20 Hz). B, original traces showing that 50 μM phenylephrine decreased the amplitude of polysynaptic eEPSCs of one neuron in a reproducible manner. Note that conduction failure was indicated by the arrow. C, Summary data show the reproducible effect of phenylephrine on the amplitude of both monosynaptic and polysynaptic eEPSCs of lamina II neurons. Data are presented as means ± S.E.M. *, P < 0.05 compared with the baseline control. Phl, phenylephrine.
Fig. 4
Fig. 4
Effect of CGP55845 on phenylephrine-induced inhibition of glutamatergic eEPSCs of lamina II neurons elicited from primary afferents. A, original traces of polysynaptic eEPSCs show the effect of phenylephrine on the amplitude of polysynaptic eEPSCs of one neuron before and during application of 2 μM CGP55845. B, Summary data show the effect of CGP55845 on phenylephrine-produced inhibition of the amplitude of both monosynaptic and polysynaptic eEPSCs of lamina II neurons. Data are presented as mean ± S.E.M. *, P < 0.05 compared with the baseline control. #, P < 0.05 compared with the value obtained with CGP55845 alone. Phl, phenylephrine; CGP, CGP55845.
Fig. 5
Fig. 5
Effect of picrotoxin on phenylephrine-produced inhibition of monosynaptic eEPSCs of lamina II neurons. A, original traces show the inhibitory effect of 50 μM phenylephrine on monosynaptic eEPSCs of one neuron before and during application of 50 μM picrotoxin. B, summary data show the effect of 50 μM picrotoxin on 50 μM phenylephrine-induced inhibition of the amplitude of monosynaptic eEPSCs of 10 neurons. Data are presented as means ± S.E.M. *, P < 0.05 compared with the baseline control. Phl, phenylephrine; PCT, picrotoxin.
Fig. 6
Fig. 6
Effect of amiloride on muscimol-induced inhibition of monosynaptic eEPSCs of lamina II neurons. A, original traces show that 500 μM amiloride blocked the effect of 0.5 μM muscimol on the amplitude of monosynaptic eEPSCs of one lamina II neuron. B, raw traces show the reproducible effect of 0.5 μM muscimol on the amplitude of monosynaptic eEPSCs of another neuron. C, group data show the effect of 500 μM amiloride on the amplitude of monosynaptic eEPSCs of 13 lamina II neurons before and druing application of 0.5 μM muscimol. D, summary data show the reproducible effect of 0.5 μM muscimol on the amplitude of monosynaptic eEPSCs of 8 neurons. Data are presented as means ± S.E.M. *, P < 0.05 compared with the baseline control. Aml, amiloride; Mus, muscimol.
Fig. 7
Fig. 7
Effect of amiloride on phenylephrine-induced inhibition of monosynaptic eEPSCs of lamina II neurons. A, original traces and summary data show the effect of 50 μM phenylephrine on the amplitude of monosynaptic eEPSCs of 11 neurons before and during application of 500 μM amiloride. B, representative traces and group data show the effect of 50 μM phenylephrine on the amplitude of monosynaptic eEPSCs of 9 neurons before and during application of 2.5 μM mibefradil. Data are presented as means ± S.E.M. *, P < 0.05 compared with the baseline control. Phl, phenylephrine; Aml, amiloride; mbf, mibefradil.
Fig. 8
Fig. 8
Effect of amiloride plus CGP55845 on pheneylephrine-produced inhibition of the amplitude of monosynaptic eEPSC of lamina II neurons. A, original traces show the effect of 50 μM phenylephrine on the amplitude of monosynaptic eEPSCs of one neuron before and during application of 500 μM amiloride alone and 500 μM amiloride plus 2 μM CGP55845. B, summary data show the effect of phenylephrine on the amplitude of monosynaptic eEPSCs before and during application of amiloride alone and amiloride plus CGP55845 (n = 4 neurons). Data are presented as means ± S.E.M. *, P < 0.05 compared with the control. Phl, phenylephrine; Aml, amiloride; CGP, CGP55845.
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