Action of dexmedetomidine on rat locus coeruleus neurones: intracellular recording in vitro.
The action of dexmedetomidine on rat locus coeruleus neurones was examined using intracellular recordings from the in vitro brain slice preparation. Concentrations of dexmedetomidine from 1 to 1000 nM were tested. At 30 nM, dexmedetomidine produced complete inhibition of firing of all neurones tested (n = 21); this was associated with a 13 mV hyperpolarization (range 2.2-29.7 mV, n = 21) and a 27% reduction in input resistance (range 11.1-46.2%, n = 17). The dexmedetomidine responses reached a plateau phase between 100 and 1000 nM. Based on single-cell recordings, the hyperpolarizing potency of dexmedetomidine was found to be 6 times greater than that of clonidine (n = 10). The reversal potential for the dexmedetomidine-induced hyperpolarization was -106.9 +/- 1.7 mV (n = 9), a value similar to the K+ equilibrium potential; hyperpolarization was blocked by both CsCl and BaCl2. The effect of dexmedetomidine was antagonized by yohimbine, with a dissociation equilibrium constant of 30 nM. In contrast, prazosin, the alpha 1-, alpha 2B- and alpha 2C-adrenoceptor subtype-preferring ligand, did not inhibit the dexmedetomidine effect. Our results also show that low concentrations of oxymetazoline (10-300 nM), an alpha 2A-adrenoceptor subtype-selective drug, cause profound inhibition of neuronal activity in the locus coeruleus. These data therefore suggest that dexmedetomidine binds to alpha 2A-adrenoceptors on the cell membrane of neurones of the locus coeruleus and that this leads to opening of the inwardly rectifying K+ channels, resulting in the observed hyperpolarization of the membrane.
Chiu
T H
TH
Department of Physiology, National Yang Ming University, Taipei, Taiwan.
Chen
M J
MJ
Yang
Y R
YR
Yang
J J
JJ
Tang
F I
FI
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D004594:Electrophysiology; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D020926:Medetomidine; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010109:Oxymetazoline / Q000494:pharmacology; D017777:Parasympathetic Fibers, Postganglionic / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015016:Yohimbine / Q000494:pharmacology
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D017609:Barium Compounds; D002712:Chlorides; D007093:Imidazoles; C024986:barium chloride; D002586:Cesium; D015016:Yohimbine; D010109:Oxymetazoline; C028019:cesium chloride; D003000:Clonidine; D020926:Medetomidine; D011224:Prazosin