Antisense technology reveals the alpha2A adrenoceptor to be the subtype mediating the hypnotic response to the highly selective agonist, dexmedetomidine, in the locus coeruleus of the rat.

Mizobe, Toshiki; Maghsoudi, Kaveh; Sitwala, Kajal; Tianzhi, Guo; Ou, Jennie; Maze, Mervyn

doi:10.1172/jci118887

Cited by 95 publications

(49 citation statements)

References 29 publications

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“…The anesthetic effect of sodium pentobarbital is mediated not by the α 2 -adrenoceptor, but rather through an enhancement of the γ-aminobutyric acid-mediated (GABA-mediated) inhibition of synaptic transmission (29). Taken together, these results indicate that PDE4D, but not PDE4B, has a modulating effect on the activity of the α 2A -adrenoceptor, the receptor subtype responsible for the hypnotic effect of α 2 -adrenoceptor agonists (19,33).…”

Section: Discussionmentioning

confidence: 86%

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Robichaud

Stamatiou²,

Jin³

et al. 2002

J. Clin. Invest.

132

140

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IntroductionCyclic nucleotides cAMP and cGMP are degraded by at least 11 families of phosphodiesterases (PDEs 1-11) classified according to their gene sequence, substrate specificity, biochemical regulation, and sensitivity to inhibitors (1, 2). The cAMP-specific PDE4 has attracted considerable attention for the treatment of airway inflammatory diseases, since its inhibition results in attenuated inflammatory responses (1,3,4). However, the therapeutic potential of PDE4 inhibitors has been limited by the side effects of nausea and emesis, observed both in humans and in various animal species following the administration of structurally diverse compounds (5-9). A major challenge in the development of new generations of PDE4 inhibitors is the improvement of the therapeutic index of this class of compounds.PDE4 enzymes use a common binuclear ion center as the core catalytic machinery (10). The reversible binding of the cation cofactors (e.g., Mg 2+ ) results in the presence of two coexisting conformers that bind inhibitors differently: the holoenzyme (enzyme bound with Mg 2+ ) and the apoenzyme (free enzyme) (11,12). In the past, it was observed that the potency of some inhibitors (e.g., rolipram) on PDE activity deviated from their affinity at the high-affinity rolipram binding site (HARBS); this led to the proposal that inhibitors with a reduced potency on the HARBS may have an improved therapeutic index over that of firstgeneration compounds (13-15). It has now been clarified that the HARBS corresponds to the holoenzyme conformer responsible for PDE4 catalysis (11,12).The PDE4 family is composed of four subtypes (PDE4A-D) and multiple splice variants (16). If it were possible to identify the subtype(s) responsible for the beneficial and the side effects associated with PDE4 inhibition, then subtype-selective inhibitors devoid of the tendency to induce nausea and vomiting could be developed. The mechanism of the emetic response associated with PDE4 inhibitors is thought to be a consequence of the inhibition of PDE4 in nontarget tissues (9, 13). It is believed that PDE4 inhibitors produce a pharmacologi- A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing α 2 -adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4- -2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice c...

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Section: Discussionmentioning

confidence: 86%

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Robichaud

Stamatiou²,

Jin³

et al. 2002

J. Clin. Invest.

132

140

View full text Add to dashboard Cite

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“…However, it has been difficult to identify whether ␣ 2 -receptors mediating sedation and hypnosis are pre-or postsynaptic receptors. According to one concept, the locus ceruleus plays an important role in the sedative effect of ␣ 2 -agonists (Mizobe et al, 1996). In mice lacking functional ␣ 2A -adrenoceptors (␣ 2A -D79N), the sedative and anesthetic-sparing effects of the ␣ 2 -agonist dexmedetomidine were ablated (Lakhlani et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

Gilsbach

Röser²,

Beetz³

et al. 2009

Molecular Pharmacology

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␣ 2 -Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether ␣ 2 -adrenoceptors on adrenergic neurons or ␣ 2 -adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of ␣ 2 -agonists, we used the dopamine ␤-hydroxylase (Dbh) promoter to drive expression of ␣ 2A -adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-␣ 2A transgenic mice were crossed with double knockout mice lacking both ␣ 2A -and ␣ 2C -receptors to generate lines with selective expression of ␣ 2A -autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express ␣ 2A -and ␣ 2C -receptors in both adrenergic and nonadrenergic cells, and ␣ 2A /␣ 2C double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to ␣ 2 -adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by ␣ 2 -receptors in nonadrenergic cells. In dopamine ␤-hydroxylase knockout mice lacking norepinephrine, the ␣ 2 -agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of ␣ 2 -adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the ␣ 2 -adrenergic receptors, and it provides important new considerations for future drug development.Adrenergic receptors are important targets for the treatment of human diseases and conditions including hypertension and heart failure, psychiatric and neurological diseases, asthma, and pain (Westfall and Westfall, 2006). To date, nine different adrenergic receptor subtypes have been cloned and grouped into three receptor groups, including ␣ 1A,B,D , ␣ 2A,B,C , and ␤ 1,2,3 (Bylund et al., 1994). However, the therapeutic potential of these subtypes has not been fully explored because of the lack of ligands with sufficient subtype-selectivity. At present, only four of the nine possible subtype distinctions (i.e., ␣ 1 , ␣ 2 , ␤ 1 , and ␤ 2 ) have achieved clinical relevance (Westfall and Westfall, 2006). Especially within the ␣ 1 -and ␣ 2 -receptor subgroups, the physiological significance of individual receptor subtypes has remained unclear until recently. For the ␣ 2 -adrenoceptors, mouse models with targeted deletions of the individual subtypes have greatly advanced our understanding of the physiological role and the therapeutic potential of these receptors (Gilsbach and Hein, 2008). Activation of ␣ 2A -receptors could be linked with bradycardia ...

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“…While most sedative drugs operate on GABA receptors, dexmedetomidine is an alpha-2 adrenergic agonist which sedates through its action at the locus coeruleus 6 . Diff e rent from GABA, alpha-2 adre n o receptors produces sedation without the entire spectrum of stupor, which may be associated with paradoxical agitation.…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine for awake craniotomy without laryngeal mask

Almeida

Tavares

Tibano

et al. 2005

Arq. Neuro-Psiquiatr.

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-O b j e c t i v e :This paper re p o rts the use of dexmedetomidine in three epileptic patients with cave rnous angiomas that underwent awake surg e ry in order to map their speech are a s . Method: L o a d i n g dose of dexmedetomidine varied from 1 µg/Kg/h to 3 µg/Kg/h over 20 minutes and maintenance dose fro m 0.4 µg/Kg/h to 0,8 µg/Kg/h. Results: There was no occurrence of hemodynamic instability, convulsions or re s p i r a t o ry depression. Patients tolerated well the pro c e d u re . Conclusion: Dexmedetomidine was useful f o r awake craniotomy as it decreased patients' level of consciousness but did not produce agitation. Lary n g e a l mask was not necessary to keep air ventilation.KEY WORDS: awake craniotomy, dexmedetomidine, epilepsy surgery, cortical mapping, neuroanesthesia.Dexmedetomidina em craniotomias com o paciente acordado sem o emprego de máscara laríngea RESUMO -O b j e t i v o :Este trabalho relata o uso de desmedetomidina em três pacientes com angiomas cavernosos próximos a área de linguagem e epilepsia que foram operados acordados para mapeamento cortical. Método: A dose de ataque de dexmedetomidina variou de 1 µg/Kg/h a 3 µg/Kg/h durante 20 minutos e dose de manutenção de 0,4 µg/Kg/h a 0,8 µg / K g / h . Resultados: Os pacientes toleraram bem o pro c e d imento e não houve instabilidade hemodinâmica, convulsões ou depressão re s p i r a t ó r i a . Conclusão: D e x m edetomidina foi útil nas craniotomias com o paciente acordado para mapeamento cortical pois gerou sedação sem agitação. A máscara laríngea não foi necessária para manter a ventilação nesses pacientes.PA L AV R A S -C H AVE: craniotomia, dexmedetomidina, ciru rgia para epilepsia, mapeamento cortical e neuro anestesia.Awake craniotomy is a useful technique when lesions near eloquent areas have to be re m o v e d 1 . U n f o rt u n a t e l y, pro c e d u re 's demands on patients a n d s u rgical team must not be neglected. Patients need to be fully alert and cooperative during testing b u t on the other hand, it is desirable to keep them sedated over the rest of surg e ry avoiding unnecess a ry discomfort and anxiety. It is a delicate balance, even on experienced hands, as re s p i r a t o rydep ression also has to be taken in account. To accomplish adequate level of sedation and analgesia both local and systemic anesthetics are used. A combination of opioids and midazolan associated, or n o t , to propofol or droperidol is effective. But, despite s a t i s f a c t o rylevel of stress for patients, small pro blems like agitation, drowsiness, seizure or pain still occur in 48% of the surgeries 2 . Dexmedetomidine hydrochloride is a selective alpha-2 adrenoceptor agonist with centrally mediated sympatholytic and sedative effects. It is indicated for sedation of intubated and mechanically ventilated patients during treatment in intensive c a reunits. Dexmedetomidine decreases the needs of analgesia and produces a kind of sedation that patient can be easily roused by verbal stimuli 3 . These characteristics brought about...

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Antisense technology reveals the alpha2A adrenoceptor to be the subtype mediating the hypnotic response to the highly selective agonist, dexmedetomidine, in the locus coeruleus of the rat.

Cited by 95 publications

References 29 publications

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Deletion of phosphodiesterase 4D in mice shortens α2-adrenoceptor–mediated anesthesia, a behavioral correlate of emesis

Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

Dexmedetomidine for awake craniotomy without laryngeal mask

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