title: Direct excitation of spinal GABAergic interneurons by noradrenaline.
abstract: Endogenous pain control is, in part, mediated by descending inhibition of spinal nociception via spinal release of noradrenaline. Antinociception by activation of descending noradrenergic fibres has partially been attributed to the direct inhibition of nociceptive spinal neurons. Here, we tested the alternative hypothesis: the direct excitation of inhibitory spinal interneurons by noradrenaline. Transverse lumbar spinal cord slices were obtained from adult mice expressing enhanced green fluorescent protein (EGFP) in GABAergic neurons under control of the GAD67 promoter. Recordings were made from a total of 113 EGFP-expressing neurons and non-EGFP-expressing neurons in spinal laminae II and III with the perforated patch-clamp technique. In lamina II, where mainly nociceptive afferents terminate, noradrenaline (20 microM) depolarised significantly more EGFP-labelled (41%) than non-EGFP-labelled GABAergic neurons (4%). In contrast, noradrenaline hyperpolarised significantly more non-EGFP-labelled (46%) than EGFP-labelled GABAergic neurons (20%). In lamina III, where low threshold afferents terminate, EGFP-labelled neurons were never depolarised but either hyperpolarised (25%) or not affected (75%) by noradrenaline. Depolarisations of EGFP-labelled lamina II neurons were mimicked by the alpha(1)-adrenoceptor agonist phenylephrine (10-20 microM) and abolished by the alpha(1)-adrenoceptor antagonist prazosin (2 microM). Hyperpolarisations of EGFP- and non-EGFP-labelled neurons were abolished by the alpha(2)-adrenoceptor antagonist yohimbine (2 microM). These results show that noradrenaline directly excites inhibitory (GABAergic) lamina II interneurons in addition to its inhibitory effect on (putatively excitatory) interneurons in superficial spinal dorsal horn. Both effects of noradrenaline constitute a synergism in descending inhibition of nociceptive information in the spinal dorsal horn.
authors.affiliation: Department of Neurophysiology, Center for Brain Research, Spitalgasse 4, A-1090 Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Gassner
authors.forename: Ruth
authors.initials: R
authors.lastname: Ruscheweyh
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sandkühler
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D018663:Adrenergic Agents / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D018756:GABA Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000172:deficiency; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D007395:Interneurons / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D013116:Spinal Cord / Q000166:cytology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018663:Adrenergic Agents; D000316:Adrenergic alpha-Agonists; D000779:Anesthetics, Local; D018756:GABA Antagonists; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine; D009638:Norepinephrine; D001640:Bicuculline