Interaction of morphine but not fentanyl with cerebral alpha2-adrenoceptors in alpha2-adrenoceptor knockout mice.
OBJECTIVE
alpha(2)-Adrenergic and mu-opioid receptors belong to the rhodopsin family of G-protein coupled receptors and mediate antinociceptive effects via similar signal transduction pathways. Previous studies have revealed direct functional interactions between both receptor systems including synergistic and additive effects. To evaluate underlying mechanisms, we have studied whether morphine and fentanyl interacted with alpha(2)-adrenoceptor-subtypes in mice lacking one individual alpha(2)-adrenoceptor-subtype (alpha(2)-adrenoceptor knockout).


METHODS
Opioid interaction 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 from alpha(2)-adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to alpha(2)-adrenoceptor subtypes in different brain regions was quantified.


RESULTS
Morphine but not fentanyl or naloxone provoked dose-dependent displacement of [(125)I]paraiodoclonidine from all alpha(2)-adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of alpha(2A)-adrenoceptor knockout mice.


CONCLUSIONS
Our results indicated that morphine interacted with alpha(2)-adrenoceptors showing higher affinity for the alpha(2B) and alpha(2C) than for the alpha(2A) subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to alpha(2)-adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.
Höcker
Jan
J
Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany. hoecker@anaesthesie.uni-kiel.de
Böhm
Ruwen
R
Meybohm
Patrick
P
Gruenewald
Matthias
M
Renner
Jochen
J
Ohnesorge
Henning
H
Scholz
Jens
J
Bein
Berthold
B
D058647:Adrenergic alpha-2 Receptor Agonists; 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; D005283:Fentanyl / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000502:physiology
C547769:Adra2a protein, mouse; C547772:Adra2b protein, mouse; C547775:Adra2c protein, mouse; D058647:Adrenergic alpha-2 Receptor Agonists; D000701:Analgesics, Opioid; D018341:Receptors, Adrenergic, alpha-2; D017450:Receptors, Opioid, mu; C053113:4-iodoclonidine; D009270:Naloxone; D009020:Morphine; D003000:Clonidine; D005283:Fentanyl