Adrenergic and Cholinergic Compounds

Sanders, Robert D.; Maze, Mervyn

doi:10.1007/978-3-540-33823-9_9

Cited by 9 publications

(5 citation statements)

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“…8). In addition to revising the view of the physiology of the adrenergic system, the present results offer new insight into the mechanisms of ␣ 2 -agonist Sanders and Maze, 2007). Antinociceptive ␣ 2 -receptors were suggested to reside in spinal terminals of primary nociceptor neurons, in spinal pain relay neurons, and on dorsal horn excitatory interneurons.…”

Section: Discussionmentioning

confidence: 73%

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

Gilsbach

Röser²,

Beetz³

et al. 2009

Mol Pharmacol

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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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Section: Discussionmentioning

confidence: 73%

“…␣ 2 -agonists mediate strong analgesic effects at spinal and supraspinal levels (Pertovaara, 2006;Sanders and Maze, 2007). Thus, we determined the antinociceptive effect of medetomidine in the tail-flick assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

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

Gilsbach

Röser²,

Beetz³

et al. 2009

Mol Pharmacol

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“…Apart from the endogenous agonists adrenaline and noradrenaline several synthetic ligands are available, including the clinically used α 2 ‐adrenoceptor agonists brimonidine, clonidine, dexmedetomidine, moxonidine, medetomidine und rilmenidine (Cambridge, 1981; Kallio et al ., 1989; Bylund et al ., 1994; Fairbanks et al ., 2009). In vivo these α 2 ‐adrenoceptor agonists elicit a wide range of effects including hypotension and bradycardia, analgesia, hypothermia, sedation, hypnosis and anaesthetic‐sparing (Hoefke and Kobinger, 1966; MacMillan et al ., 1996; Lakhlani et al ., 1997; Kamibayashi and Maze, 2000; Scholz and Tonner, 2000; Maze et al ., 2001; Lahdesmaki et al ., 2003; Knaus et al ., 2007b; Sanders and Maze, 2007a). However, some of these effects limit the clinical applicability of current non‐subtype‐selective α 2 ‐adrenoceptor agonists.…”

Section: α2‐adrenoceptor Subtypesmentioning

confidence: 99%

Are the pharmacology and physiology of α₂adrenoceptors determined by α₂‐heteroreceptors and autoreceptors respectively?

Gilsbach¹,

Hein

2011

British J Pharmacology

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a2-Adrenoceptors are important mediators of physiological responses to the endogenous catecholamines noradrenaline and adrenaline. In addition, a2-adrenoceptors are pharmacological targets for the treatment of hypertension, sympathetic overactivity and glaucoma. a2-Adrenoceptors are also targeted to induce sedation and analgesia in anaesthesia and intensive care. a2-Adrenoceptors were first described as presynaptic receptors inhibiting the release of various transmitters from neurons in the central and peripheral nervous systems. In addition to these presynaptic neuronal receptors, a2-adrenoceptors were also identified in many non-neuronal cell types of the body. Gene-targeting in mice provided a comprehensive assignment of the physiological and pharmacological functions of these receptors to specific a2A-, a2B-and a2C-adrenoceptor subtypes. However, the specific cell types and signalling pathways involved in these subtype-specific a2-adrenoceptor functions were largely unexplored until recently. This review summarizes recent findings from transgenic mouse models, which were generated to define the role of a2-adrenoceptors in adrenergic neurons, that is, a2-autoreceptors, versus a2-adrenoceptors in nonadrenergic neurons, termed a2-heteroreceptors. a2-Autoreceptors are primarily required to limit release of noradrenaline from sympathetic nerves and adrenaline from adrenal chromaffin cells at rest. These receptors are desensitized upon chronic activation as it may for instance occur due to enhanced sympathetic activity during chronic heart failure. In contrast, pharmacological effects of acutely administered a2-adrenoceptor agonist drugs essentially require a2-heteroreceptors in non-adrenergic neurons, including analgesia, sedation, hypothermia and anaesthetic-sparing as well as bradycardia and hypotension. Thus a clear picture has emerged of the significance of auto-versus heteroreceptors in mediating the physiological functions of a2-adrenoceptors and the pharmacological functions of a2-adrenoceptor agonist drugs respectively. AbbreviationsDbh, dopamine-b hydroxylase; GRK2, G-protein receptor kinase 2 IntroductionThe a2-adrenoceptor family comprising a2A-, a2B-and a2C-subtypes was identified by pharmacological (Cheung et al., 1982;Latifpour et al., 1982;Summers et al., 1983;Feller and Bylund, 1984;Neylon and Summers, 1985) and molecular cloning techniques (Kobilka et al., 1987;Regan et al., 1988;Lomasney et al., 1990). All three a2-adrenoceptor subtypes are coupled to G-proteins of the Gai/o family and therefore share general signalling properties (Limbird, 1988). a2-Adrenoceptors were first discovered as presynaptic receptors in neurons inhibiting the exocytosis of several neurotransmitters (for review, see Starke, 2001). Depending on the location of the a2-adrenoceptor and the neurotransmitter that is modulated by these receptors, the terms 'autoreceptors' and 'heteroreceptors' were introduced. 'Autoreceptors' refers to a2-adrenoceptors, which are located in the presynaptic membrane of adrenergic neurons, thus...

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“…Especially, α 2 -adrenergic receptors are densely expressed in dorsal and ventral horns of the spinal cord. The activation of spinal α 2 -adrenergic receptors exerts several pharmacological profiles such as hypotension, hypothermia, hypnosis, analgesia and sedation [ 18 19 20 21 22 23 ]. We recently found that the activation of α 2 -adrenergic receptors located in the spinal cord elevates the blood glucose level [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

The activation of α₂-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

Kim

Park

Lee

et al. 2017

Korean J Physiol Pharmacol

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The effect of clonidine administered intrathecally (i.t.) on the mortality and the blood glucose level induced by sepsis was examined in mice. To produce sepsis, the mixture of D-galactosamine (GaLN; 0.6 g/10 ml)/lipopolysaccharide (LPS; 27 µg/27 µl) was treated intraperitoneally (i.p.). The i.t. pretreatment with clonidine (5 µg/5 µl) increased the blood glucose level and attenuated mortality induced by sepsis in a dose-dependent manner. The i.t. post-treatment with clonidine up to 3 h caused an elevation of the blood glucose level and protected sepsis-induced mortality, whereas clonidine post-treated at 6, 9, or 12 h did not affect. The pre-treatment with oral D-glucose for 30 min prior to i.t. post-treatment (6 h) with clonidine did not rescue sepsis-induced mortality. In addition, i.t. pretreatment with pertussis toxin (PTX) reduced clonidine-induced protection against mortality and clonidine-induced hyperglycemia, suggesting that protective effect against sepsis-induced mortality seems to be mediated via activating PTX-sensitive G-proteins in the spinal cord. Moreover, pretreatment with clonidine attenuated the plasma tumor necrosis factor α (TNF-α) induced by sepsis. Clonidine administered i.t. or i.p. increased p-AMPKα1 and p-AMPKα2, but decreased p-Tyk2 and p-mTOR levels in both control and sepsis groups, suggesting that the up-regulations of p-AMPKα1 and p-AMPKα2, or down-regulations of p-mTOR and p-Tyk2 may play critical roles for the protective effect of clonidine against sepsis-induced mortality.

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Adrenergic and Cholinergic Compounds

Cited by 9 publications

References 73 publications

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

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

Are the pharmacology and physiology of α₂adrenoceptors determined by α₂‐heteroreceptors and autoreceptors respectively?

The activation of α₂-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

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Adrenergic and Cholinergic Compounds

Cited by 9 publications

References 73 publications

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

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

Are the pharmacology and physiology of α2adrenoceptors determined by α2‐heteroreceptors and autoreceptors respectively?

The activation of α2-adrenergic receptor in the spinal cord lowers sepsis-induced mortality

Contact Info

Product

Resources

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

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

Are the pharmacology and physiology of α₂adrenoceptors determined by α₂‐heteroreceptors and autoreceptors respectively?

The activation of α₂-adrenergic receptor in the spinal cord lowers sepsis-induced mortality