title: Meperidine, remifentanil and tramadol but not sufentanil interact with alpha(2)-adrenoceptors in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor knock out mice brain.
abstract: alpha(2)-adrenoceptor agonists like clonidine or dexmedetomidine increase the sedative and analgesic actions of opioids. Furthermore opioids like meperidine show potent anti-shivering effects like alpha(2)-adrenoceptor agonists. The underlying molecular mechanisms of these effects are still poorly defined. The authors therefore studied the ability of four different opioids (meperidine, remifentanil, sufentanil and tramadol) to interact with different alpha(2)-adrenoceptor subtypes in mice lacking individual alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptors (alpha(2)-adrenoceptor knock out (alpha(2)-AR KO) mice)). The interaction of opioids with alpha(2)-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of alpha(2A)-, alpha(2B)- or alpha(2C)-adrenoceptor deficient mice. Displacement of the radiolabelled alpha(2)-adrenoceptor agonist [(125)I]-paraiodoclonidine ([(125)I]-PIC) from alpha(2)-adrenoceptors in different brain regions by increasing opioid concentrations was measured, and binding affinity of the analysed opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified. Meperidine, remifentanil and tramadol but not sufentanil provoked dose dependent displacement of specifically bound [(125)I]-PIC from all alpha(2)-adrenoceptor subtypes in cortex, cerebellum, medulla oblongata, thalamus, hippocampus and pons. Required concentrations of meperidine and remifentanil for [(125)I]-PIC displacement from alpha(2B)- and alpha(2C)-adrenoceptors were lower than from alpha(2A)-adrenoceptors, indicating higher binding affinity for alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, [(125)I]-PIC displacement by tramadol indicated higher binding affinity to alpha(2A)-adrenoceptors than to alpha(2B)- and alpha(2C)-adrenoceptors. Our results indicate that meperidine, remifentanil and tramadol interact with alpha(2)-adrenoceptors in mouse brain showing different affinity for alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors. In contrast, the micro-agonist sufentanil did not show any alpha(2)-adrenoceptor interaction. These effects may have an impact on the pharmacologic actions of these opioids.
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany. jhoecker@web.de
authors.forename: Jan
authors.initials: J
authors.lastname: Höcker
authors.forename: Bernd
authors.initials: B
authors.lastname: Weber
authors.forename: Peter H
authors.initials: PH
authors.lastname: Tonner
authors.forename: Jens
authors.initials: J
authors.lastname: Scholz
authors.forename: Philipp-Alexander
authors.initials: PA
authors.lastname: Brand
authors.forename: Henning
authors.initials: H
authors.lastname: Ohnesorge
authors.forename: Berthold
authors.initials: B
authors.lastname: Bein
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000345:Affinity Labels / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D054333:Drug Partial Agonism; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008614:Meperidine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010880:Piperidines / Q000494:pharmacology; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics; D000077208:Remifentanil; D017409:Sufentanil / Q000494:pharmacology; D014147:Tramadol / Q000494:pharmacology
chemical_list: C547769:Adra2a protein, mouse; C547772:Adra2b protein, mouse; C547775:Adra2c protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D000345:Affinity Labels; D000701:Analgesics, Opioid; D010880:Piperidines; D018341:Receptors, Adrenergic, alpha-2; C053113:4-iodoclonidine; D014147:Tramadol; D008614:Meperidine; D017409:Sufentanil; D003000:Clonidine; D000077208:Remifentanil