Pharmacology of serotonin as related to anesthesia

doi:10.1016/0952-8180(96)00093-1

Journal of Clinical Anesthesia

Volume 8, Issue 5, August 1996, Pages 402-425

https://doi.org/10.1016/0952-8180(96)00093-1 Get rights and content

Abstract

Serotonin (5-hydroxytryptamine) is an important biogenic amine that fulfills the role of neurotransmitter and neuromodulator. It has been a focus of interest during the last decade. Its diversity of pharmacologic actions is related to a wide variety of receptors and effector mechanisms. Seven serotonin receptor families have been identified thus far. They are genetically different transmembrane proteins composed of several hundred amino acids. The majority of these are G-protein-coupled, except the 5-HT₃ receptors, which are directly ligand gated to fast ion channels. Serotonin is widely distributed in the body within the central and peripheral nervous systems, smooth muscles, and platelets, in particular. Consequently, its effects manifest mainly in these organs and influence a wide variety of neural, vascular, smooth muscle, and platelet functions. (Melatonin, a physiologically active metabolite of serotonin, is also instrumental in affecting many neural and hormonal functions.)

Several selective agonists and particularly many selective antagonists have been developed for serotonin, which helped the serotonin receptor subtype classification. Some of these drugs are also used therapeuticatty in the treatment of migraine (eg, sumatriptan, which is a 5-HT₁ receptor agonist), vascular disorders (5-HT₂ antagonists), and nausea and vomiting (5-HT₃ antagonists, eg, dolasetron, granisetron, ondansetron, and tropisetron), and have been investigated in gastrointestinal motility disorders (5-HT₄ antagonists) and behavioral psychopathologies (5-HT₁ agonists and 5-HT_2–4 antagonists). Serotonin reuptake inhibitors are of particular clinical importance in the treatment of psychological illnesses. Future use of these drugs is also envisioned in the treatment of certain types of pain syndromes.

Awareness of the serotonergic drugs and the recognition of possible drug interactions among drugs that influence serotonergic mechanisms in humans are becoming increasingly important in the practice of anesthesiology.

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Increased epinephrine may be caused by decreased venous return due to sitting position and stimulation of the carotid baroreceptors (endogenous epinephrine). Hypovolemia not only causes stimulation of cardiac mechanoreceptors in the left ventricle that triggers the BJR and causes reflex bradycardia, vasodilatation and hypotension [19–22], but also results in the activation of thrombocytes to release serotonin which triggers chemoreceptors in the wall of the heart [12,21,23]. Furthermore, stimulation of 5-HT3 receptors, that are G protein coupled, ligand-gated, fast-ion channels, increases the activity of the vagal nerve [21].
This study was conducted to test whether blocking the serotonin receptors by intravenous [IV] ondansetron; can help in reducing the hypotensive bradycardic events [HB events] associated with shoulder arthroscopy done in the sitting position under interscalene plexus block [ISB].
One hundred and fifty patients, scheduled for shoulder arthroscopy in the sitting position under ISB, were randomly assigned to one of three groups receiving either: 4 mg ondansetron, or 8 mg ondansetron or saline.
IV injection of ondansetron 4 mg or 8 mg significantly reduced the incidence of HB events from 20.4% in the saline group to 6.1% after injection of 4 mg ondansetron and 6% after injection of 8 mg ondansetron; p value [0.030].
IV ondansetron either 4 mg or 8 mg reduces the HB events during shoulder arthroscopy in the sitting position under ISB.
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A sensitive and novel electrochemical method has been developed for the determination of an important neurotransmitter, serotonin, using a polymelamine modified edge plane pyrolytic graphite sensor (EPPGS). Melamine was used for the modification of sensor by electropolymerizing it at the surface of EPPGS in acidic medium to form a layer of conducting polymer. Field emission scanning electron microscopy (FE-SEM) and electrochemical impedance spectroscopy (EIS) were used for the characterization of the surface of polymer modified sensor. The electrochemical measurements were carried out using square wave voltammetry and cyclic voltammetry. The polymelamine modified sensor exhibited excellent electrocatalytic activity towards the electrochemical oxidation of serotonin, exhibiting a larger peak current and shift of peak potential to less positive potentials as compared to the unmodified sensor. The dynamic range for the serotonin determination was found between 1–100 µm and 0.1–100 µm with detection limit of 492 nM and 30 nM for unmodified and polymer modified sensors, respectively. The determination of serotonin in human blood serum and urine has been carried out. The common metabolites such as ascorbic acid, dopamine, xanthine and hypoxanthine do not interfere in the determination up to 10-fold concentration, revealing good selectivity of the proposed sensor.
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Subarachnoid block is the preferred method of anaesthesia for caesarean section, but is associated with hypotension and bradycardia, which may be deleterious to both parturient and baby. Animal studies suggest that in the presence of decreased blood volume, 5-HT may be an important factor inducing the Bezold Jarisch reflex via 5-HT3 receptors located in intracardiac vagal nerve endings. In this study, we evaluated the effect of ondansetron, as a 5-HT3 receptor antagonist, on the haemodynamic response following subarachnoid block in parturients undergoing elective caesarean section.
Fifty-two parturients scheduled for elective caesarean section were randomly allocated into two groups. Before induction of spinal anaesthesia Group O (n = 26) received intravenous ondansetron 4 mg; Group S (n = 26) received normal saline. Blood pressure, heart rate and vasopressor requirements were assessed.
Decreases in mean arterial pressure were significantly lower in Group O than Group S from 14 min until 35 min. Patients in Group O required significantly less vasopressor (P = 0.009) and had significantly lower incidences of nausea and vomiting (P = 0.049).
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Side effects of spinal anesthesia include arterial hypotension and bradycardia. Both of them may be induced by sympathetic nerve blockade as well as by the Bezold-Jarisch reflex, which may be mediated by peripheral serotonin receptors (5-HT₃ type). The aim of this study was to verify the hypothesis that blockade of type 3 serotonin receptors by intravenous ondansetron administration might reduce hypotension and bradycardia induced by spinal anesthesia.
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The serotonergic system may play a role during general anesthesia but the effect of the volatile anesthetic halothane on the release of serotonin (5-HT) is not fully understood. Rat brain cortical slices were labeled with [³H]5-HT to investigate the effects of halothane on the release of this neurotransmitter from the central nervous system. Halothane induced an increase on the release of [³H]5-HT that was dependent on incubation time and anesthetic concentration (0.006, 0.012, 0.024, 0.036, 0.048 and 0.072 mM). This effect was independent of extracellular calcium and was not affected by tetrodotoxin (blocker of voltage dependent Na⁺ channels). In contrast, the halothane-evoked [³H]5-HT release was reduced by BAPTA-AM, a membrane-permeable BAPTA analog that chelates intracellular Ca²⁺. The anesthetic-induced [³H]5-HT release depends on the ryanodine-sensitive intracellular calcium store since it was blocked by dantrolene and azumolene (inhibitors of the calcium-release through ryanodine receptors) but was not affected by aminoethoxydiphenylborate (2-APB), an inhibitor of inositol 1,4,5-triphosphate receptor. The [³H]5-HT release induced by halothane comes mainly from the vesicular pool since it was reduced in about 70% by reserpine, a blocker of vesicular monoamine transporter. The halothane-evoked release of [³H]5-HT release is reduced by fluoxetine, an inhibitor of 5-HT uptake, and the volatile agent also decreased the uptake of [³H]5-HT into rat brain cortical slices. Moreover, a decrease on halothane-induced release of [³H]5-HT was also observed when the brain cortical slices were incubated at low temperature, which is known to interfere with the carrier-mediated release of the neurotransmitter. Ouabain, a Na⁺/K⁺ ATPase pump inhibitor, which induces 5-HT release through reverse transport, also decreased [³H]5-HT release induced by halothane, confirming the involvement of a carrier-mediated release of the neurotransmitter in the presence of halothane. In conclusion, these data suggest that halothane induces vesicular and carrier-mediated release of [³H]5-HT in rat brain cortical slices.

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Pharmacology of serotonin as related to anesthesia

Abstract

J Biol Chem

Trends Pharmacol Sci

Biol Psychiatry

Lancet

Eur J Pharmacol

Br J Anaesth

Trends Pharmacol Sci

Br J Anaesth

Cancer Treatment Rev

Lancet

Lancet

Lancet

Trends Pharmacol Sci

Pharmacol Biochem Behav

Eur J Pharmacol

Lancet

Br J Anaesth

Trends Pharmacol Sci

Eur J Pharmacol

Pharmacology of indolealkylamines

Pharmacol Rev

Serotonin (5-hydroxytryptamine)

Physiol Rev

Evidence for the participation of serotonin in mental process

Ann NY Acad Sci

Serotonin LSD interactions

Ann NY Acad Sci

Serotonin containing neurons in the brain: depression of firing by monoamine oxidase inhibitors

Science

Multiple serotonin receptors: differential binding of (H3) 5-hydroxytryptamine (3H) lysergic acid diethylamide and (3H) spiroperidol

Mol Pharmacol

Pineal melatonin: cell biology of its synthesis and of its physiological interactions

Endo Rev

Melatonin receptors

Ann Rev Pharmacol Toxicol

Isolation of melatonin, the pineal gland factor that lightens melanocytes

J Am Chem Soc

Melatonin as a free radical scavenger: implications for aging and age-related diseases

New molecules active at the melatonin receptor level

Development of melatonin analogues

Chronobiological activity of melatonin. Mediation by gabaergic mechanisms

Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors

J Pharmacol Exp Ther

5-Hydroxytryptamine receptors

Pharmacol Rev

Chimaeric nicotinic serotoninergic receptor combines distinct ligand binding and channel specificities

Nature

Serotonin receptors: from genes to pathology

Serotonergic mechanisms in age-related cognitive impairment and dementias

Pharmacology of central serotonin neurons

Ann Rev Pharmacol Toxicol

Imipramine binding: its relationship with serotonin uptake and depression

Pharmacology of sertraline: a review

J Clin Psychiatry

Electrophysiological aspects of serotonin neuropharmacology. Implications for antidepressant treatments

Critical issues in defining the role of serotonin in psychiatric disorders

Pharmacol Rev

Presynaptic serotonin receptors in the central nervous system

Ann NY Acad Sci

Desensitization by antidepressants of central norepinephrine receptor systems coupled to adenylate cyclase

Ann NY Acad Sci

The paradox of neurochemical and clinical properties of serotonergic antidepressants

Multiple serotonin receptors: differential binding of (H³) 5-hydroxytryptamine (³H) lysergic acid diethylamide and (³H) spiroperidol