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Further characterization of the ORL 1 receptor‐mediated inhibition of noradrenaline release in the mouse brain in vitro
Author(s) -
Werthwein Sven,
Bauer Ulrich,
Nakazi Michael,
Kathmann Markus,
Schlicker Eberhard
Publication year - 1999
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0702534
Subject(s) - nociceptin receptor , chemistry , (+) naloxone , endocrinology , medicine , agonist , receptor , rauwolscine , serotonin , monoamine neurotransmitter , opioid peptide , antagonist , opioid , biochemistry , biology , prazosin
Mouse brain slices preincubated with [ 3 H]‐noradrenaline or [ 3 H]‐serotonin were superfused with medium containing naloxone 10 μ M ; we studied whether nociceptin (the endogenous ligand at ORL 1 receptors) affects monoamine release. Furthermore, the affinities of ORL 1 ligands were determined using [ 3 H]‐nociceptin binding. The electrically (0.3 Hz) evoked tritium overflow in mouse cortex slices preincubated with [ 3 H]‐noradrenaline was inhibited by nociceptin and [Tyr 14 ]‐nociceptin (maximally by 80%; pEC 50 7.52 and 8.28) but not affected by [des‐Phe 1 ]‐nociceptin (pEC 50 <6). The ORL 1 antagonist naloxone benzoylhydrazone antagonized the effect of nociceptin and [Tyr 14 ]‐nociceptin. The effect of nociceptin did not desensitize, was not affected by blockade of NO synthase, cyclo‐oxygenase and P 1 ‐purinoceptors and was decreased by the α 2 ‐adrenoceptor agonist talipexole. Nociceptin also inhibited the evoked overflow in mouse cerebellar, hippocampal and hypothalamic slices in a manner sensitive to naloxone benzoylhydrazone. The electrically (3 Hz) evoked tritium overflow in mouse cortex slices preincubated with [ 3 H]‐serotonin was inhibited by nociceptin; naloxone benzoylhydrazone antagonized this effect. The affinities (pK i ) for [ 3 H]‐nociceptin binding to mouse cortex membranes were: nociceptin, 8.71; [Tyr 14 ]‐nociceptin, 9.82; [des‐Phe 1 ]‐nociceptin, <5.5; naloxone benzoylhydrazone, 5.85; naloxone, <4.5. In conclusion, nociceptin inhibits noradrenaline release in the mouse cortex via ORL 1 receptors, which interact with presynaptic α 2 ‐autoreceptors on noradrenergic neurones. The effect of nociceptin does not desensitize nor does it involve NO, prostanoids or adenosine. Nociceptin also attenuates noradrenaline release from several subcortical regions and serotonin release from cortical slices by a naloxone benzoylhydrazone‐sensitive mechanism.British Journal of Pharmacology (1999) 127 , 300–308; doi: 10.1038/sj.bjp.0702534