The &agr;2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects

  title={The \&agr;2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects},
  author={Laura E. Nelson and Jun Lu and Tian Z. Guo and Clifford B. Saper and Nicholas P. Franks and M Maze},
Background The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective &agr;2-adrenoceptor agonist) activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways. Methods c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and in situ hybridization. Next, the authors perturbed these pathways using (1) discrete lesions induced by ibotenic acid, (2) local and systemic… 

Bidirectional Regulation of Intravenous General Anesthetic Actions by &agr;3-containing &ggr;-aminobutyric AcidA Receptors

The results indicate that &agr;3-containing GABAA receptors on noradrenergic neurons may contribute to this constraint of anesthetic actions of compounds with targets partly or exclusively distinct from GAB AA receptors such as medetomidine, ketamine, and pentobarbital.

Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine &bgr;-Hydroxylase Knockout Mice

The loss of norepinephrine and epinephrine and not other neuromodulators co-packaged in adrenergic neurons is sufficient to cause hypersensitivity to induction of volatile anesthesia and Dexmedetomidine-induced general anesthesia does not depend on inhibition of adrenergic neurotransmission.


It is reported that noradrenergic projections from the locus oeruleus to the forebrain are not necessary for the wakeromoting action of modafinil, a commonly used agent for the treatment of excessive sleepiness.

Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems

How two different classes of sedatives can selectively interact with some nodal points of the circuitry that promote wakefulness allowing the transition to NREM sleep is reviewed to aid the design of more precise acting sedatives, and reveal more about the natural sleep-wake circuitry.

Corticotropin-releasing Factor Mediates the Antinociceptive Action of Nitrous Oxide in Rats

Nitrous oxide activates the CRF system in the brain, which results in stimulation of noradrenergic neurons in the locus ceruleus and its consequent antinociceptive effect.

Bidirectional Regulation of Intravenous General Anesthetic Actions by α 3-containing γ -aminobutyric Acid A Receptors

In mice lacking the α 3 subunit of the GABA A receptor ( α 3 knockout), the increases of the hypnotic and immobilizing actions induced by ket-amine/xylazine were largely absent, whereas the increase in the hypothermic action was still present.

Oral Delivered Dexmedetomidine Promotes and Consolidates Non-rapid Eye Movement Sleep via Sleep–Wake Regulation Systems in Mice

Results indicate that orally delivered dexmedetomidine can induce sedative and hypnotic effects by exciting the sleep-promoted nucleus and inhibiting the wake-promoting areas.

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

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, suggesting that the sedative qualities of dexmedETomidine and its effect on the thalamocortical network are not decisively shaped by direct inhibition ofHCN channel function.



Nitrous oxide produces antinociceptive response via alpha2B and/or alpha2C adrenoceptor subtypes in mice.

These data confirm that the antinociceptive response to an exogenous alpha2-agonist is mediated by an alpha2A adrenoceptor and that there appears to be a role for the alpha2B- or alpha2C-adrenoceptor subtypes, or both, in the analgesic response to N2O.

A Hypnotic Response to Dexmedetomidine, an α2 Agonist, Is Mediated in the Locus Coerüleus in Rats

The present data suggest that alpha 2-adrenergic receptors in the LC appear to be a major site for the hypnotic action of dexmedetomidine.

Perturbation of Ion Channel Conductance Alters the Hypnotic Response to the α2-Adrenergic Agonist Dexmedetomidine in the Locus Coeruleus of the Rat

Inhibition of ion conductance through L- or Ptype calcium channels and facilitation of Conductance through voltage-gated or calcium-activated potassium channels may be involved in the mechanism of hypnotic action of α2-adrenergic agonists.

The sedative component of anesthesia is mediated by GABAA receptors in an endogenous sleep pathway

It is concluded that the tuberomammillary nucleus (TMN) is a discrete neural locus that has a key role in the sedative response to GABAergic anesthetics.

Assessment of the role of α2‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice

1 The role of α2‐adrenoceptor (AR) subtypes in the modulation of acute nociception, motor behaviour and body temperature, has been investigated by determining the activity of the α2AR selective

Evidence for histaminergic arousal mechanisms in the hypothalamus of cat

Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system.

  • E. MacdonaldM. Scheinin
  • Biology
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
  • 1995
By examining the distribution of the mRNA coding for the three subtypes of the alpha 2-adrenoceptor, it has been possible to map those regions in the brain which possess cells which synthetize the distinct subtypes.

Substitution of a mutant alpha2a-adrenergic receptor via "hit and run" gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo.

It is demonstrated that alpha2AR agonist-elicited sedative, anesthetic-sparing, and analgesic responses are lost in a mouse line expressing a subtly mutated alpha2AAR, D79N alpha2 aAR, created by two-step homologous recombination, providing definitive evidence that the alpha1AAR subtype is the primary mediator of clinically important central actions of alpha2 AR agonists.

Histaminergic descending inputs to the mesopontine tegmentum and their role in the control of cortical activation and wakefulness in the cat

It is hypothesized that the histaminergic descending afferents in the MPT would promote cortical desynchronization and W, at least partially, via activation of H1 receptors situated on cholinergic neurons and that the interactions between Histaminergic and cholin allergic neurons constitute an important circuit in cortical activation during W.