Sedative Properties of Dexmedetomidine Are Mediated Independently from Native Thalamic Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function at Clinically Relevant Concentrations

Abstract

Dexmedetomidine is a selective α2-adrenoceptor agonist and appears to disinhibit endogenous sleep-promoting pathways, as well as to attenuate noradrenergic excitation. Recent evidence suggests that dexmedetomidine might also directly inhibit hyperpolarization-activated cyclic-nucleotide gated (HCN) channels. We analyzed the effects of dexmedetomidine on native HCN channel function in thalamocortical relay neurons of the ventrobasal complex of the thalamus from mice, performing whole-cell patch-clamp recordings. Over a clinically relevant range of concentrations (1–10 µM), the effects of dexmedetomidine were modest. At a concentration of 10 µM, dexmedetomidine significantly reduced maximal Ih amplitude (relative reduction: 0.86 [0.78–0.91], n = 10, and p = 0.021), yet changes to the half-maximal activation potential V1/2 occurred exclusively in the presence of the very high concentration of 100 µM (−4,7 [−7.5–−4.0] mV, n = 10, and p = 0.009). Coincidentally, only the very high concentration of 100 µM induced a significant deceleration of the fast component of the HCN activation time course (τfast: +135.1 [+64.7–+151.3] ms, n = 10, and p = 0.002). With the exception of significantly increasing the membrane input resistance (starting at 10 µM), dexmedetomidine did not affect biophysical membrane properties and HCN channel-mediated parameters of neuronal excitability. Hence, the sedative qualities of dexmedetomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition of HCN channel function.

The feasibility of dexmedetomidine-led anesthesia maintenance strategy during major abdominal surgery

“…2. Dexmedetomidine acts on central presynaptic and postsynaptic α2 receptors in specific brain regions involved in sleep and wakefulness regulation, such as the locus coeruleus, and impacts endogenous sleep-promoting pathways [ 24 , 25 ]. 3.…”

Modulating Hyperpolarization-Activated Cation Currents through Small Molecule Perturbations: Magnitude and Gating Control

“…Dexmedetomidine (Precedex ® , (S)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole), a lipophilic imidazole derivative, is viewed as a potent and selective agonist of the α2-adrenergic receptor [ 49 , 50 , 51 ]. Previous studies have revealed that this drug exerts a variety of actions on the human brain, such as sedation, anesthetic-sparing effects, and analgesia [ 52 , 53 , 54 ]. However, there is evidence to highlight the notion that direct interactions with membrane ionic channels may be an unidentified but important mechanism underlying dexmedetomidine-induced action in central neurons [ 28 , 53 , 55 , 56 , 57 ].…”

“…Previous studies have revealed that this drug exerts a variety of actions on the human brain, such as sedation, anesthetic-sparing effects, and analgesia [ 52 , 53 , 54 ]. However, there is evidence to highlight the notion that direct interactions with membrane ionic channels may be an unidentified but important mechanism underlying dexmedetomidine-induced action in central neurons [ 28 , 53 , 55 , 56 , 57 ]. In particular, in pituitary GH 3 cells, dexmedetomidine produced a depressant action on I h in a concentration- and time-dependent fashion, with an IC 50 or K D value of 1.21 or 1.97 μM, respectively [ 28 ].…”

“…This implies that, besides its known ability to bind to α2-adrenergic receptors, dexmedetomidine may directly influence the activation process of the HCN channel, thereby modifying the magnitude and kinetics of I h in response to prolonged membrane hyperpolarization. Additionally, the blockade of I h induced by dexmedetomidine could serve as a significant ionic mechanism that effectively reduces the intrinsic membrane excitability of neurons, as well as neuroendocrine or endocrine cells, in vivo [ 7 , 28 , 52 , 53 , 54 , 55 , 58 ].…”

“…However, it needs to be noted that the sedative properties of dexmedetomidine and its effects on the thalamocortical network might not be primarily influenced by the direct inhibition of I h . This implies that dexmedetomidine likely acts through other mechanisms, such as α 2 -adrenoceptor activation and modulation of noradrenergic excitation, to exert its sedative effects [ 53 ].…”