Interactions of anesthetics with their targets: Non-specific, specific or both?

Urban, B. W.; Bleckwenn, Markus; Barann, Martin

doi:10.1016/j.pharmthera.2005.12.005

Cited by 73 publications

(78 citation statements)

References 280 publications

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“…Approximately 10-fold higher concentrations were required for propofol to induce a tonic GABAergic current. Our NTS data suggest that the sensitivity of phasic GABA A receptors to propofol in this adult tissue corresponds to estimated therapeutic concentrations (Rudolph & Antkowiak, 2004;Urban et al, 2006;Franks, 2006) and these mechanisms may well contribute to the autonomic dysregulation observed in patients that includes baroreflex depression and sympathoinhibition (Ebert et al, 1992;Ebert, 2005) as in animal models (Seagard et al, 1983;Lee et al, 2002).…”

Section: Discussionmentioning

confidence: 57%

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

et al. 2008

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The anesthetic propofol is thought to induce rapid hypnotic sedation by facilitating a GABAergic tonic current in forebrain neurons. The depression of cardiovascular and respiratory regulation often observed during propofol suggests potential additional actions within the brainstem. Here we determined the impacts of propofol on both GABAergic and glutamatergic synaptic mechanisms in a class of solitary tract nucleus (NTS) neurons common to brainstem reflex pathways. In horizontal brainstem slices, we recorded from NTS neurons directly activated by solitary tract (ST) axons. We identified these second-order NTS neurons by time-invariant ("jitter" <200 µs), "all-or-none" glutamatergic excitatory postsynaptic currents (EPSCs) in response to shocks to the ST. In order to assess propofol actions, we measured ST-evoked, spontaneous and miniature EPSCs and inhibitory postsynaptic currents (IPSCs) during propofol exposure. Propofol prolonged miniature IPSC decay time constants by 50% above control at 1.8 µM. Low concentrations of gabazine (SR-95531) blocked phasic GABA currents. At higher concentrations, propofol (30 µM) induced a gabazine-insensitive tonic current that was blocked by picrotoxin or bicuculline. In contrast, total propofol concentrations up to 30 µM had no effect on EPSCs. Thus, propofol enhanced phasic GABA events in NTS at lower concentrations than tonic current induction, opposite to the relative sensitivity observed in forebrain regions. These data suggest that therapeutic levels of propofol facilitate phasic (synaptic) inhibitory transmission in second order NTS neurons which likely inhibits autonomic reflex pathways during anesthesia.

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Section: Discussionmentioning

confidence: 57%

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

et al. 2008

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“…Despite the prevalence of its use, the fundamental question of what the functional target of propofol in the human brain is remains unanswered (Urban, 2002;Urban et al, 2006). The neural mechanisms underlying propofol-induced behavioral changes such as loss of consciousness and amnesia are particularly investigated (Kennedy and Norman, 2005;Schneider and Kochs, 2007).…”

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confidence: 99%

The Action Sites of Propofol in the Normal Human Brain Revealed by Functional Magnetic Resonance Imaging

Zhang¹,

Wang²,

Zhao³

et al. 2010

The Anatomical Record

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Propofol has been used for many years but its functional target in the intact brain remains unclear. In the present study, we used functional magnetic resonance imaging to demonstrate blood oxygen level dependence signal changes in the normal human brain during propofol anesthesia and explored the possible action targets of propofol. Ten healthy subjects were enrolled in two experimental sessions. In session 1, the Observer's Assessment of Alertness/Sedation Scale was performed to evaluate asleep to awake/alert status. In session 2, images with blood oxygen level dependence contrast were obtained with echo-planar imaging on a 1.5-T Philips Gyroscan Magnetic Resonance System and analyzed. In both sessions, subjects were intravenously administered with saline (for 3 min) and then propofol (for 1.5 min) and saline again (for 10.5 min) with a constant speed infusion pump. Observer's Assessment of Alertness/Sedation Scale scoring showed that the subjects experienced conscious-sedative-unconscious-analepsia, which correlated well with the signal decreases in the anesthesia states. Propofol induced significant signal decreases in hypothalamus (18.2% AE 3.6%), frontal lobe (68.5% AE 11.2%), and temporal lobe (34.7% AE 6.1%). Additionally, the signals at these three sites were fulminant and changed synchronously. While in the thalamus, the signal decrease was observed in 5 of 10 of the subjects and the magnitude of decrease was 3.9% AE 1.6%. These results suggest that there is most significant inhibition in hypothalamus, frontal lobe, and temporal in propofol anesthesia and moderate inhibition in thalamus. These brain regions might be the targets of propofol anesthesia in human brain. Anat Rec, 293:1985Rec, 293: -1990

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“…10], in which several ligand-gated ion channels and a wide range of anesthetics have been pooled, was used to predict anesthetic IC 50 values (in mol/l): log (IC 50 uncharged drug ) ϭ Ϫ1.568 Ϫ 0.9898 ϫ log (P octanol/water ).…”

Section: Calculation Of Lipophilicity and Predicted Ic 50 Valuesmentioning

confidence: 99%

“…In order to decide whether the effects on 5-HT 3A receptors were nonspecific, specific or both [ Figure 12b in Ref. 10], we compared the experimental drug potencies at 5-HT 3A receptors with those exclusively predicted by drug lipophilicities. To decide whether a possible specific site on 5-HT 3A receptors might be similar to a recognition site on opioid receptors, we compared the rank order of opioid potencies at 5-HT 3A receptors with that at opioid receptors (Table 1).…”

mentioning

confidence: 99%

The Effects of Fentanyl-Like Opioids and Hydromorphone on Human 5-HT3A Receptors

Wittmann

Schaaf

Peters

et al. 2008

Anesthesia &Amp; Analgesia

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Only morphine and hydromorphone, but not the fentanyl derivatives, reduced 5-HT-induced current amplitudes and slowed current kinetics near clinically relevant concentrations. The high potencies of morphine and hydromorphone, when compared to their lipophilicities, suggest a specific interaction with 5-HT(3A) receptors. In contrast, the effects of fentanyl-type opioids appear to be of unspecific nature. Because the rank order of opioid potencies for human 5-HT(3A) receptors is opposite of that for opioid receptors, the site involved is structurally different from opioid receptor binding sites. In agreement with recent data on different phenols, a phenolic OH-group (which morphine and hydromorphone possess) may contribute to specific interactions of morphine and hydromorphone with the 5-HT(3A) receptor. Future clinical studies could test whether corresponding differences in emetogenicity between different classes of opioids will be found.

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Interactions of anesthetics with their targets: Non-specific, specific or both?

Cited by 73 publications

References 280 publications

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

The Action Sites of Propofol in the Normal Human Brain Revealed by Functional Magnetic Resonance Imaging

The Effects of Fentanyl-Like Opioids and Hydromorphone on Human 5-HT3A Receptors

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