Stimulation of α1 -adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABAA receptors and T-type Ca2+ channels

Abstract Activation of the descending noradrenergic system inhibits nociceptive transmission in the spinal cord. Although both α1 - and α2 -adrenoceptors in the spinal cord are involved in the modulation of nociceptive transmission, it is not clear how α1 -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 α1 -adrenoceptor agonist phenylephrine significantly increased the frequency of GABAergic spontaneous IPSCs in a concentration dependent manner, and this effect was abolished by the α1 -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 GABAA receptor antagonist picrotoxin and, to a lesser extent, by the GABAB receptor antagonist CGP55845. Furthermore, blocking T-type Ca2+ channels with amiloride or mibefradil diminished the inhibitory effect produced by phenylephrine or the GABAA receptor agonist muscimol on monosynaptic EPSCs evoked from primary afferents. Collectively, these findings suggest that activation of α1 -adrenoceptors in the spinal cord increases synaptic GABA release, which attenuates glutamatergic input from primary afferents mainly through GABAA receptors and T-type Ca2+ channels. This mechanism of presynaptic inhibition in the spinal cord may be involved in the regulation of nociception by the descending noradrenergic system.