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

@article{Nelson2003TheA,
  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},
  journal={Anesthesiology},
  year={2003},
  volume={98},
  pages={428-436}
}
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
TLDR
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.
&agr;2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons
TLDR
Hippocampal SV exocytosis is inhibited by &agr;2A-AR activation in proportion to reduced Ca2+ entry and these effects are additive with those of isoflurane, consistent with a role for &agre;2a-AR presynaptic heteroreceptor inhibition of nonadrenergic synaptic transmission in the anesthetic-sparing effects of &agR;2 A-AR agonists.
Supraclinical concentrations of dexmedetomidine evoke norepinephrine release from rat cerebrocortical slices Possible involvement of the orexin-1 receptor
Dexmedetomidine is a highly selective alpha(2)-agonist and reduces norepinephrine release from several neuronal tissues. However, supraclinical concentrations of dexmedetomidine have been reported to
Dexmedetomidine Enhances Analgesic Action of Nitrous Oxide: Mechanisms of Action
TLDR
The synergistic analgesic interaction between nitrous oxide and dexmedetomidine within the spinal cord is obscured by a supraspinal antagonism when dexmedETomidine is administered systemically in the pretolerant state.
Hypnotic Hypersensitivity to Volatile Anesthetics and Dexmedetomidine in Dopamine &bgr;-Hydroxylase Knockout Mice
TLDR
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.
OPAMINERGIC–ADRENERGIC INTERACTIONS IN THE WAKE ROMOTING MECHANISM OF MODAFINIL
bstract—Adrenergic signaling regulates the timing of sleep tates and sleep state-dependent changes in muscle tone. ecent studies indicate a possible role for noradrenergic ransmission in the
Dopaminergic—adrenergic interactions in the wake promoting mechanism of modafinil
TLDR
It is reported that noradrenergic projections from the locus coeruleus to the forebrain are not necessary for the wake-promoting action of modafinil, and this findings implicate non-noradrenaline, dopamine-dependent adrenergic signaling in the wake -promoting mechanism of modfinil.
Sleep and Sedative States Induced by Targeting the Histamine and Noradrenergic Systems
TLDR
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
TLDR
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.
Oral Delivered Dexmedetomidine Promotes and Consolidates Non-rapid Eye Movement Sleep via Sleep–Wake Regulation Systems in Mice
TLDR
Results indicate that orally delivered dexmedetomidine can induce sedative and hypnotic effects by exciting the sleep-promoted nucleus and inhibiting the wake-promoting areas.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 51 REFERENCES
Nitrous oxide produces antinociceptive response via alpha2B and/or alpha2C adrenoceptor subtypes in mice.
TLDR
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
TLDR
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
TLDR
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
TLDR
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
Inhibition of adenylate cyclase in the locus coeruleus mediates the hypnotic response to an alpha 2 agonist in the rat.
TLDR
It is determined that the transduction mechanism for the hypnotic response to dexmedetomidine, a highly selective alpha 2 agonist, resides in the locus coeruleus (LC) of the rat, and candidates for the effector mechanism include inhibition of adenylate cyclase and cAMP-specific phosphodiesterase inhibitor.
Evidence for histaminergic arousal mechanisms in the hypothalamus of cat
TLDR
The results suggest that histaminergic systems in the hypothalamus play an important role in arousal mechanisms and their actions are mediated through H1-receptors.
Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system.
  • E. Macdonald, M. Scheinin
  • Biology, Medicine
    Journal of physiology and pharmacology : an official journal of the Polish Physiological Society
  • 1995
TLDR
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.
TLDR
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.
A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats
TLDR
The present data support the hypotheses that the posterior hypothalamus plays a critical role in the mechanisms of W and that sleep might result from functional blockade of the hypothalamic waking center.
...
1
2
3
4
5
...