Interaction of morphine but not fentanyl with cerebral α2-adrenoceptors in α2-adrenoceptor knockout mice

Abstract

Abstract Objectives α2-Adrenergic and μ-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 α2-adrenoceptor-subtypes in mice lacking one individual α2-adrenoceptor-subtype (α2-adrenoceptor knockout). Methods Opioid interaction with α2-adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of α2A-, α2B- or α2C-adrenoceptor deficient mice. Displacement of the radiolabelled α2-adrenoceptor agonist [125I]paraiodoclonidine from α2-adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to α2-adrenoceptor subtypes in different brain regions was quantified. Key findings Morphine but not fentanyl or naloxone provoked dose-dependent displacement of [125I]paraiodoclonidine from all α2-adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of α2A-adrenoceptor knockout mice. Conclusions Our results indicated that morphine interacted with α2-adrenoceptors showing higher affinity for the α2B and α2C than for the α2A subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to α2-adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.