title: Stimulation of alpha(1)-adrenoceptors reduces glutamatergic synaptic input from primary afferents through GABA(A) receptors and T-type Ca(2+) channels.
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.
authors.affiliation: Department of Anesthesiology and Pain Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: W-X
authors.initials: WX
authors.lastname: Yuan
authors.forename: S-R
authors.initials: SR
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.forename: H-L
authors.initials: HL
authors.lastname: Pan
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology*; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000502:physiology*; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D009118:Muscimol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000584:Amiloride; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004146:Dioxanes; D018755:GABA Agonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D020748:Mibefradil; D009118:Muscimol; D010656:Phenylephrine; D010721:Phosphinic Acids; D010852:Picrotoxin; D011412:Propanolamines; D018340:Receptors, Adrenergic, alpha-1; D011963:Receptors, GABA-A; C085075:CGP 55845A; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane