title: Comparison of the ORL1 receptor-mediated inhibition of noradrenaline release in human and rat neocortical slices.
abstract: The effects of nociceptin/orphanin (N/OFQ) and the selective ORL1 antagonist J-113397 (1-[(3R,4R)-1-cyclo-octylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one) were studied on electrically-evoked release of [(3)H]-noradrenaline ([(3)H]-NA) from human and rat neocortical slices. Specimens of human tissue were obtained during neurosurgery. Slices were preincubated with 0.1 microM [(3)H]-NA, superfused in the presence of desipramine, idazoxan, and naloxone (1 microM each), and stimulated electrically up to three times under conditions (4 pulses, 100 Hz, 2 ms, 60 mA) that prevent inhibition of evoked [(3)H]-NA release by endogenous modulators accumulating during ongoing stimulation. N/OFQ decreased electrically-evoked [(3)H]-NA release in both human and rat neocortical slices in a concentration-dependent manner. The respective pEC(50) values were 7.74 [CI(95): 7.47, 8.04] and 7.64 [CI(95): 7.48, 7.77], and the maximal inhibitions were 36.9% [CI(95): 32.4%, 41.8%] and 66.4% [CI(95): 61.7%, 72.7%]. N/OFQ (1 microM) inhibited K(+) (15 mM)-evoked [(3)H]-NA release from neocortical slices of both species by a similar magnitude, either in the presence or absence of tetrodotoxin. The nonpeptide ORL1 antagonist J-113397 competitively attenuated, with similar potency, the inhibition of electrically-evoked [(3)H]-NA release by N/OFQ in both species (pA(2) values: human, 8.16 [CI(95): 7.64, 8.64]; rat, 8.47 [CI(95): 8.27, 8.67]). J-113397 (0.1 microM) by itself did not alter either the evoked or spontaneous [(3)H]-NA release, suggesting that presynaptic ORL1 receptors are not activated by endogenous N/OFQ under the stimulation conditions employed. This study provides the first evidence that N/OFQ modulates [(3)H]-NA release in human neocortex via specific ORL1 receptors most likely located on noradrenergic axon terminals.
authors.affiliation: Sektion Klinische Neuropharmakologie der Neurologischen Universitätsklinik, Neurozentrum, Breisacherstr. 64, D-79106 Freiburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
authors.forename: Stefan
authors.initials: S
authors.lastname: Förster
authors.forename: Josef
authors.initials: J
authors.lastname: Zentner
authors.forename: David J
authors.initials: DJ
authors.lastname: Dooley
authors.forename: Alexander T
authors.initials: AT
authors.lastname: McKnight
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Feuerstein
authors.forename: Rolf
authors.initials: R
authors.lastname: Jackisch
authors.forename: Mila
authors.initials: M
authors.lastname: Vlaskovska
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002648:Child; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018847:Opioid Peptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D001562:Benzimidazoles; D009292:Narcotic Antagonists; D009638:Norepinephrine; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397