Meperidine, remifentanil and tramadol but not sufentanil interact with α2-adrenoceptors in α2A-, α2B- and α2C-adrenoceptor knock out mice brain

α2-adrenoceptor agonists like clonidine or dexmedetomidine increase the sedative and analgesic actions of opioids. Furthermore opioids like meperidine show potent anti-shivering effects like α2-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 α2-adrenoceptor subtypes in mice lacking individual α2A-, α2B- or α2C-adrenoceptors (α2-adrenoceptor knock out (α2-AR KO) mice)). The interaction of opioids 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 ([125I]-PIC) from α2-adrenoceptors in different brain regions by increasing opioid concentrations was measured, and binding affinity of the analysed opioids to α2-adrenoceptor subtypes in different brain regions was quantified. Meperidine, remifentanil and tramadol but not sufentanil provoked dose dependent displacement of specifically bound [125I]-PIC from all α2-adrenoceptor subtypes in cortex, cerebellum, medulla oblongata, thalamus, hippocampus and pons. Required concentrations of meperidine and remifentanil for [125I]-PIC displacement from α2B- and α2C-adrenoceptors were lower than from α2A-adrenoceptors, indicating higher binding affinity for α2B- and α2C-adrenoceptors. In contrast, [125I]-PIC displacement by tramadol indicated higher binding affinity to α2A-adrenoceptors than to α2B- and α2C-adrenoceptors. Our results indicate that meperidine, remifentanil and tramadol interact with α2-adrenoceptors in mouse brain showing different affinity for α2A-, α2B- and α2C-adrenoceptors. In contrast, the µ-agonist sufentanil did not show any α2-adrenoceptor interaction. These effects may have an impact on the pharmacologic actions of these opioids.