Interaction of morphine but not fentanyl with cerebral α 2 ‐adrenoceptors in α 2 ‐adrenoceptor knockout mice

Objectives α 2 ‐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 α 2 ‐adrenoceptor‐subtypes in mice lacking one individual α 2 ‐adrenoceptor‐subtype (α 2 ‐adrenoceptor knockout). Methods Opioid interaction with α 2 ‐adrenoceptors was investigated by quantitative receptor autoradiography in brain slices of α 2A ‐, α 2B ‐ or α 2C ‐adrenoceptor deficient mice. Displacement of the radiolabelled α 2 ‐adrenoceptor agonist [ 125 I]paraiodoclonidine from α 2 ‐adrenoceptors in different brain regions by increasing concentrations of morphine, fentanyl and naloxone was analysed. The binding affinity of both opioids to α 2 ‐adrenoceptor subtypes in different brain regions was quantified. Key findings Morphine but not fentanyl or naloxone provoked dose‐dependent displacement of [ 125 I]paraiodoclonidine from all α 2 ‐adrenoceptor subtypes in the brain regions analysed. Binding affinity was highest in cortex, medulla oblongata and pons of α 2A ‐adrenoceptor knockout mice. Conclusions Our results indicated that morphine interacted with α 2 ‐adrenoceptors showing higher affinity for the α 2B and α 2C than for the α 2A subtype. In contrast, fentanyl and naloxone did not show any relevant affinity to α 2 ‐adrenoceptors. This effect may have an impact on the pharmacological actions of morphine.