Supraclinical concentrations of dexmedetomidine evoke norepinephrine release from rat cerebrocortical slicesPossible involvement of the orexin-1 receptor

Abstract

Dexmedetomidine is a highly selective α2-agonist and reduces norepinephrine release from several neuronal tissues. However, supraclinical concentrations of dexmedetomidine have been reported to increase norepinephrine release from cardiac stores. In addition, some report using microdialysis shows that intrathecal clonidine increased norepinephrine release from the dorsal horn in mid-thoracic spinal cord but dexmedetomidine did not. Thus, in the present study we have studied effects of dexmedetomidine on norepinephrine release from rat cerebrocortical slices and compared this with clonidine. We have also used a selective α2-antagonist yohimbine and an orexin-1 receptor antagonist SB-334867 to examine whether the effects of dexmedetomidine on norepinephrine release are mediated via α2-adrenergic or orexin (OX) receptors. In addition, concentrations of orexin A in the evoked sample were also measured. Dexmedetomidine significantly increased norepinephrine release (basal = 100%) from rat cerebrocortical slices in a concentration-dependent manner with Emax 377.3 ± 8.6% and pEC50 6.12 ± 0.07, whereas clonidine significantly reduced the release with Emax 62.1 ± 6.8% and pEC50 4.55 ± 0.25. Yohimbine (10−5 M) did not affect the concentration–response curve of dexmedetomidine for norepinephrine release. However, SB-334867 concentration-dependently antagonized dexmedetomidine-evoked norepinephrine release with Imax 91.0 ± 9.4% and pIC50 5.99 ± 0.18. Orexin A concentrations did not differ between the samples. Thus, supraclinical concentrations of dexmedetomidine increase norepinephrine release from rat cerebrocortical slices, and this release may be mediated via OX1 but not α2-adrenoceptors.