Inhibitory Effect Of Serotonin Research Articles

Mechanisms Involved in the Stimulatory and Inhibitory Effects of 5-Hydroxytryptamine on Vagal Mechanosensitive Afferents in Rat Lung.

Mechanosensitive vagal afferents in the lung, rapidly and slowly adapting receptors (RARs and SARs, respectively), play an important role in eliciting the reflexes that regulate the normal airway function. A profound bronchoconstrictive effect of 5-hydroxytryptamine (5-HT) has been extensively reported in various animal species, but its influence on the SAR and RAR activity is not known. This study investigated the effect of 5-HT on these receptors, and the possible mechanisms involved. Single-fiber activities of these afferents were measured in anesthetized, open-chest, and mechanically ventilated rats. Our results showed that intravenous injection of 5-HT evoked a consistent and pronounced stimulation of phasic RARs. In contrast, 5-HT generated an inconsistent and paradoxical action on SARs: no effect in 29% (5 of 17) of the SARs; stimulation in 35% (6 of 17); and inhibition in the remainder. These responses of both RARs and SARs to 5-HT were reproducible and dose-dependent. After the injection of a high dose of 5-HT (16 μg/kg), the receptor responses slowly reached a peak (after ∼8 s) and returned toward the baseline in ∼20 s, accompanied by a consistent increase in total pulmonary resistance and a decrease in dynamic lung compliance in a temporal pattern very similar to the increased receptor activity. When these changes in lung mechanics induced by 5-HT were prevented by pretreatment with salbutamol, a β2 adrenergic receptor agonist, the delayed responses of both RARs and SARs to 5-HT were also abolished, except that the immediate stimulatory effect on a subset of RARs, the silent RARs, was not affected. In conclusion, 5-HT generated a delayed stimulatory effect on RARs and a paradoxical effect on SARs, which resulted primarily from the 5-HT-induced changes in mechanical properties of the lung.

Clinical and biochemical features of anxiety in children with hyperkinetic disorder

Clinical and biochemical features of anxiety in children with a hyperkinetic disorder, also known as a combined type of ADHD, have not been studied, although these data are extremely necessary for therapeutic intervention in cases of comorbidity of hyperkinetic and anxiety disorders.Objective: to study pathogenetic mechanisms and the role of anxiety level in the formation of the main symptoms of the disorder.Materials and methods. We examined 182 children with hyperkinetic disorder and 60 peers from control group aged 6–10 years. After clinical examination we studied the content of monoamines, their precursors, and metabolic products in daily urine. Assessment of the main clinical symptoms (inattention, hyperactivity, impulsivity) was carried out on the SNAP-IV scale. An assessment of the level of anxiety was carried out according to the questionnaire Lavrentieva G.P. and Titarenko T.M. Patients with hyperkinetic disorder were divided into subgroups according to the nature of the monoaminergic “profile”.The results of the study support the hypothesis that pathological and steady increase in anxiety level leads to increase in the impulsivity level in children with hyperkinetic disorder. And the main role in this process is played by the noradrenergic system and the weakening of the inhibitory effect of serotonin, causing an increase of anxiety level and aggravating the imbalance of the activity of monoamine systems.

Synergistic effects of serotonin and D-lys3- GHRP-6 on food intakes in food deprived male rats

Serotonin exerts an inhibitory effect on food intakes. D-Lys3 -GHRP-6 is a ghrelin receptor antagonist which inhibits fasting or ghrelin- induced food intake. In the present study, the effects of serotonin on food intakes were investigated in D-Lys 3 - GHRP-6- treated food-deprived male rats. Twenty food-deprived male rats in four groups (5 in each) received third cerebral ventricular injection of saline, 10µg serotonin, 20nmol D-Lys 3 -GHRP-6 or combination of D-Lys 3 -GHRP-6 and serotonin respectively. Mean of one hour food intakes were measured. Data was analyzed by one-way analysis of variance (ANOVA) with post hoc Tukey’s test. In all cases, P<0.05 was considered to be statistically significant. Serotonin, D-Lys 3 - GHRP-6 or combination of serotonin/D-Lys 3 - GHRP-6 decreased the mean food intakes significantly when compared to saline. A significant decrease was observed on mean food intakes between combination of D-Lys 3 -GHRP-6 and serotonin group and serotonin or D-Lys 3 - GHRP-6 groups. A significant decrease was not observed on food intakes between serotonin and D-Lys 3 - GHRP-6 groups. Serotonin and D-Lys 3 -GHRP-6 may exert synergistic inhibitory effects on food intake in rats. Decrease of the ghrelin pathway activity may have a role in mediating the inhibitory effects of serotonin on food intakes.

Serotonin abrogates dopamine induced aggregation of cytochrome c

Importance of cytochrome c arises from its involvement in apoptosis, sequence homology and conserveness during molecular evolution. Dopamine at 25μM concentration for 30h resulted in cytochrome c aggregation as evident by increase in ANS and ThT binding, structural transition from α helix to β sheet and shift in congo red assay. Interestingly, serotonin at 25μM concentration incubated for 60h abrogates the aggregatory effect on cytochrome c. Fibrillation of human cytochrome c in the presence of dopamine gives the clue about conformational changes taking place in protein and example of natural aggregation and inhibitory effect of serotonin gives the clue about natural defence mechanism occurring in human body.

The effect of prolonged intranasal administration of serotonin on the activity of hypothalamic signaling systems in male rats with neonatal diabetes

The functioning of the serotonergic system of the brain is impaired in type II diabetes (T2D), and this leads to metabolic and hormonal dysfunction. The elevation of serotonin level in the CNS is one of the approaches for correcting of the serotonergic system of the brain. The aim of the present work was to investigate the effect of intranasal serotonin (InS) administration for 5 weeks at a daily dose of 20 μg on the metabolic parameters and functional activity of adenylate cyclase signaling system (ACSS) sensitive to peptide hormones and biogenic amines in the hypothalamus of male rats with neonatal T2D. Neonatal model of T2D was induced by injecting streptozotocin (70 mg/kg) into 5-day-old rat pups. Four-month-old animals with apparent T2D manifestations were divided into two groups: an untreated group (D0, n = 6) and a group that received InS treatment (DIS, n = 6). InS administration to diabetic rats restored ACSS regulation by the agonists of type 2 dopamine receptors (DA2R) and type 4 melanocortin receptors (MC4R) and enhanced the inhibitory effect of serotonin on adenylate cyclase activity. Elevated expression of genes encoding DA2R, MC4R, and serotonin receptor of the 1B subtype (5-HT1BR) was among the main causes of this change. The relative activity of signaling cascades involving various types of serotonin (Gs-coupled 5-HT4,6,7R/Gi-coupled 5-HT1R), dopamine (DA1R/ DA2R), and melanocortin (MC3R/MC4R) receptors involved in ACSS regulation was also altered in the animals of the DIS group. InS administration restored hormonal regulation in the hypothalamus, improved glucose tolerance, and increased the sensitivity of tissues to insulin. The data obtained show that the elevation of serotonin level in the CNS is a promising approach for the recovery of hypothalamic signaling pathways in T2D and correction of the metabolic disturbances dependent on these pathways.

Tryptophan Supplementation in the Pharmacotherapy of Anorexia Nervosa

The significance of diet in human health, behavior and therapeutics is becoming increasingly recognized. All amino acids, being building blocks to the synthesis of proteins, are critical for life, but scientific interest on the role of tryptophan, an essential amino acid, in the modulation of behavior and treatment of brain disorders emerged because tryptophan is the precursor of neurotransmitter 5-hydroxytryptamine (5-HT; serotonin). Tryptophan hydroxylase, the rate limiting enzyme of serotonin biosynthesis exists unsaturated with its substrate under normal physiological conditions. It can be speculated that tryptophan supplementation could boost serotonin synthesis and neurotransmission and may be effective in the treatment of serotonin deficiency disorder. Anorexia nervosa, an eating disorder, characterized by false body perception, intense fear of weight gain, hyperactivity and amenorrhea is associated with high risk of mortality. Excessive starvation and exercise in anorexia nervosa, despite its negative consequences, parallels some features of addiction. Evidence suggests that the efficacy of pharmacotherapy in anorexia nervosa is not satisfactory. This article draws attention towards improving pharmacotherapy in anorexia nervosa by tryptophan supplementation. Studies performed in our laboratory on rat models show that excessive dietary restriction and starvation decreases serotonin neurotransmission, firstly by decreasing the nutritional availability of the essential amino acid tryptophan, the precursor of serotonin and secondarily by an increase in the effectiveness of feedback control over the synthesis and release of serotonin. A deficiency of serotonin produces depression like effects while the release of dopamine neurotransmission from the inhibitory effects of serotonin may lead to hyperactivity and addiction like behavior observed in anorexia nervosa patients. It is suggested that tryptophan supplementation can improve efficacy of pharmacotherapy in anorexia nervosa by increasing availability of precursor for serotonin synthesis and normalizing feedback control over serotonin synthesis and release.

Sleep deprivation enhances peripheral serotonin secretion to regulate the large follicle steroidogenesis of rats

ObjectiveSleep deprivation (SD) leads to the disturbance of the estrous cycle. Serotonin, the levels of which increase with SD, has been shown to inhibit luteinizing hormone production and the receptor has been found in the follicles. In this study, the serotonin effect on preovulatory follicular steroidogenesis is investigated and the underlying mechanisms are elucidated. Materials and methodsFemale rats were subjected to SD for a time span of 1–4 days using the dish-over-water-method with a Rechtschaffen apparatus. Serum estradiol and serotonin concentrations were assessed; thereafter, they were evaluated with the effect of serotonin on the estradiol production and steroidogenic acute regulatory (StAR) protein expression in a serum-free culture system. Preovulatory follicles were dissected mechanically from the ovaries of 21-day-old rats, which induced follicle growth, and cultured for 24 hours with or without recombinant human follicle-stimulating hormone (FSH) in the presence or absence of serotonin. ResultsSD, led to a significant decrease in serum estradiol concentrations, while serotonin concentrations were significantly elevated (all p < 0.05). Follicles were cultured with a constant dose of FSH (50 mIU/mL) and increasing doses of serotonin, estradiol production was reduced by 20%. The inhibitory effect of serotonin was concentration dependent. The addition of serotonin (0.1 μg/mL) decreased FSH-induced estradiol production and attenuated FSH-stimulated follicular StAR protein expression. The inhibitory effects of serotonin could be reduced by the serotonin receptor antagonist ketanserin. ConclusionThese findings suggest that decreased serum estradiol concentrations in SD rats may be the result of serotonin-related inhibition of estradiol production and decreased large follicle expression of StAR protein.

Inhibiting peripheral serotonin synthesis reduces obesity and metabolic dysfunction by promoting brown adipose tissue thermogenesis.

Mitochondrial uncoupling protein 1 (UCP1) is enriched within interscapular brown adipose tissue (iBAT) and beige (also known as brite) adipose tissue, but its thermogenic potential is reduced with obesity and type 2 diabetes for reasons that are not understood. Serotonin (5-hydroxytryptamine, 5-HT) is a highly conserved biogenic amine that resides in non-neuronal and neuronal tissues that are specifically regulated via tryptophan hydroxylase 1 (Tph1) and Tph2, respectively. Recent findings suggest that increased peripheral serotonin and polymorphisms in TPH1 are associated with obesity; however, whether this is directly related to reduced BAT thermogenesis and obesity is not known. We find that Tph1-deficient mice fed a high-fat diet (HFD) are protected from obesity, insulin resistance and nonalcoholic fatty liver disease (NAFLD) while exhibiting greater energy expenditure by BAT. Small-molecule chemical inhibition of Tph1 in HFD-fed mice mimics the benefits ascribed to Tph1 genetic deletion, effects that depend on UCP1-mediated thermogenesis. The inhibitory effects of serotonin on energy expenditure are cell autonomous, as serotonin blunts β-adrenergic induction of the thermogenic program in brown and beige adipocytes in vitro. As obesity increases peripheral serotonin, the inhibition of serotonin signaling or its synthesis in adipose tissue may be an effective treatment for obesity and its comorbidities.

The role of glutamatergic and GABAergic systems on serotonin- induced feeding behavior in chicken

It has been reported that serotonin can modulate glutamate and GABA release in central nervous system (CNS). The present study was designed to examine the role of glutamatergic and GABAergic systems on serotonin- induced feeding behavior in chickens. In Experiment 1 intracerebroventricular (ICV) injection of MK- 801(NMDA receptor antagonist, 15 nmol) performed followed by serotonin (10 μg). In experiments 2, 3, 4, 5, 6 and 7 prior to serotonin injection, chickens received CNQX (AMPA/kainate receptor antagonist, 390 nmol), AIDA (mGluR1 antagonist, 2 nmol), LY341495 (mGluR2 antagonist, 150 nmol), UBP1112 (mGluR3 antagonist, 2 nmol), picrotoxin (GABA A receptor antagonist, 0.5 μg), CGP54626 (GABAB receptor antagonist, 20 ng) respectively. Cumulative food intake was determined at 3 h post injection. The results of this study showed that the hypophagic effect of serotonin was significantly attenuated by pretreatment with MK- 801 and CNQX (p < 0.05) but AIDA, LY341495 and UBP1112 had no effect (p > 0.05). Also, the inhibitory effect of serotonin on food intake was amplified by picrotoxin (p < 0.05) while CGP54626 had no effect (p > 0.05). These results suggest that serotonin as a modulator probably interacts with glutamatergic (via NMDA and AMPA/Kainate receptors) and GABAergic (via GABAA receptor) systems on feeding behavior in chicken.

The effect of melanocortin (Mc3 and Mc4) antagonists on serotonin-induced food and water intake of broiler cockerels

The current study was designed to examine the effects of intracerebroventricular injections of SHU9119 [a nonselective melanocortin receptor (McR) antagonist] and MCL0020 (a selective McR antagonist) on the serotonin-induced eating and drinking responses of broiler cockerels deprived of food for 24 h (FD24). For Experiment 1, the chickens were intracerebroventricularly injected with 2.5, 5, and 10 µg serotonin. In Experiment 2, the chickens received 2 nmol SHU9119 before being injected with 10 µg serotonin. For Experiment 3, the chickens were given 10 µg serotonin after receiving 2 nmol MCL0020, and the level of food and water intake was determined 3 h post-injection. Results of this study showed that serotonin decreased food intake but increased water intake among the FD24 broiler cockerels and that these effects occurred in a dose-dependent manner. The inhibitory effect of serotonin on food intake was significantly attenuated by pretreatment with SHU9119 and MCL0020. However, the stimulatory effect of serotonin on water intake was not altered by this pretreatment. These results suggest that serotonin hypophagia and hyperdipsia were mediated by different mechanisms in the central nervous system, and that serotonin required downstream activation of McRs to promote hypophagia but not hyperdipsia in the FD24 chickens.

Inhibitory effect of 5-hydroxytryptamine on rat stomach fundus: mediated indirectly by activation of noradrenaline release.

Biphasic cumulative concentration-response curves to 5-hydroxytryptamine (5-HT) and alpha-methyl-5-hydroxytryptamine (alpha-Me-5-HT) using rat stomach fundus in the presence of 50 microM pargyline suggested two sites of interaction (high and low affinity). The order of agonist potencies of 5-HT agonists for the high-affinity (contractile) response confirmed reports of a strong correlation of the 5-HT2B (contractile) receptor on fundus with reported rat brain (radioligand binding) pKd values at the 5-HT2C receptor (r = 0.94, b = 0.93 P < 0.01). 1(1-Naphthyl)-piperazine and ketanserin antagonized the high-affinity responses. The order of potencies for the low affinity (inhibitory) response was: alpha-Me-5-HT > 5-HT. Preincubation with mianserin or S-(-)propranolol, pretreatment with reserpine and removal of the mucosa layer resulted in amplification of the contractile effects and disappearance or reversal of the inhibitory effects of 5-HT. Activation of a second receptor site inducing catecholamine release may explain this effect of 5-HT on rat stomach fundus.

Inhibitory effect of 5-hydroxytryptamine on lipogenesis in rat adipose tissues.

5-Hydroxytryptamine (5-HT) inhibited the incorporation of 14C from 14C-labelled glucose, pyruvate, citrate and acetate into fatty acids but it did not inhibit the conversion of 14C from citrate and acetate into CO2, and the citrate conversion into glyceride-glycerol in epididymal and mesenteric adipose tissue from 24h-fasted rats. 5-HT stimulated the formation of lactate from glucose and pyruvate, and increased the ratio of lactate produced/pyruvate taken up. This ratio was similar to the NADH:NAD ratio. These results indicate that 5-HT inhibits fatty acid synthesis in rat white adipose tissue by mechanisms similar to those of the catecholamines.

Functional state of adenylyl cyclase signaling system in reproductive tissues of rats with experimental type-1 diabetes

Diabetes mellitus (DM) of type 1 induces numerous disturbances in reproductive systems of males and females. We have shown earlier that the main cause of the complications in the case of DM is alteration of adenylyl cyclase signaling system (ACSS) sensitivity to hormones. The aim of the present work was identification of disturbances in hormone-regulated ACSS in reproductive tissues of rats with experimental type 1 DM (EDM1) induced by streptozotocin treatment. Testis of the rats with 5-days EDM1 showed significant decrease in the stimulatory effects of human chorionic gonadotropin (hCG) and PACAP-38 on adenyly] cyclase (AC) activity and G protein GTP-binding. Uterus of the rats with EDM1 exhibited decreased effects of relaxin, PACAP-38 and biogenic amines. In the ovaries, we showed the decrease in hCG effects only. Weakening of the inhibitory influence of somatostatin on ACSS activity was found in all studied tissues of rats with EDM1. Uterus displayed also decreased inhibitory effects of serotonin and adrenaline. Thus, regulatory effects of the hormones in ACSS sensitivity in reproductive tissues of the rats with EDM1 were decreased. The effects of hCG and AC inhibiting hormones were decreased to a greater extent. We suppose that the decrease in ACSS sensitivity to hormones in the case of EDM1 is responsible for pathological changes in reproductive systems of diabetic rats under condition of hyperglycemia and insulin deficiency which are typical for type 1 DM.

The Peptides Mimicking the Third Intracellular Loop of 5-Hydroxytryptamine Receptors of the Types 1B and 6 Selectively Activate G Proteins and Receptor-Specifically Inhibit Serotonin Signaling via the Adenylyl Cyclase System

The third intracellular loop (ICL3) of G protein-coupled receptors has, as a rule, a key role in their interaction with heterotrimeric G proteins. We synthesized peptides corresponding to the C-terminal region of the ICL3 (C-ICL3) of 5-hydroxytryptamine receptors of the type 1B (5-HT1BR) and 6 (5-HT6R) and studied their influence on the functional activity of adenylyl cyclase signaling system (ACSS) in synaptosomal membranes isolated from the rat brain. The 5-HT1BR-peptide ARERKATKTL307–316K-amide mimicking agonist-activated 5-HT1BR reduced forskolin-stimulated adenylyl cyclase (AC) activity and activated pertussis toxin-sensitive G proteins. It lowered inhibitory effects of serotonin and 5-HT1BR-agonists on forskolin-stimulated AC activity and their stimulating effects on GTP binding. This was not the case in the presence of 5-HT1BR-antagonists. The 5-HT6R-peptides mimicking 5-HT6R activated both the basal AC activity and GTP binding of cholera toxin-sensitive G proteins. They lowered the stimulating effect of serotonin and 5-HT6R-agonists on AC and Gs proteins, but in the presence of 5-HT6R-antagonists their action was blocked. Of all the 5-HT6R-peptides with linear and dimeric structure we studied the palmitoylated peptide KHSRKALKASL258–268K(Pal)A-amide had a most pronounced effect both on the basal and 5-HT6R-agonist-stimulated ACSS. The data was obtained indicating that the peptides corresponding to C-ICL3 of 5-HT1BR and 5-HT6R selectively activate Gi and Gs proteins, respectively, and in a receptor-specific manner reduce signal transduction via serotonin-sensitive ACSS in the rat brain. The results of the study give strong evidence in favor of active participation of C-ICL3 of these 5-HTRs in their coupling with the G proteins.

Effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone in Wistar rats

The effect of serotonin on the formation of neurons producing gonadotropin-releasing hormone (GnRH) during embryogenesis of Wistar rats was studied. The neurons producing GnRH were detected immunocytochemically on days 18 and 21 of embryonic development and on day 15 of postnatal development of rats with normal serotonin metabolism and rats in which the synthesis of serotonin was inhibited by p-chlorophenylalanine. The total number of GnRH neurons in serotonin deficiency was larger than in the case of its normal metabolism at all developmental stages studied. This is an indirect evidence for the inhibitory effect of serotonin on the formation ofGnRH neurons. To confirm the morphogenetic effect of serotonin, we studied the rate of formation of GnRH neurons by injecting bromodeoxyuridine in the formation period of these neurons. It was found that serotonin deficiency had no effect on the time of formation of GnRH neurons: over 97% of neurons formed on days 11 to 15 of embryonic development both in the experimental and control groups. Note that, in serotonin deficiency, the maximum number of GnRH neurons formed one day later than in the normal state. Thus, serotonin inhibits the proliferation of GnRH neuron progenitor cells and thereby has a morphogenetic effect on the development of these neurons.

Serotonin and Sleep: Molecular, Functional, and Clinical Aspects

Serotonin and Sleep: Molecular, Functional, and Clinical Aspects

Some effects of dopamine transporter and receptor ligands on discriminative stimulus, physiologic, and directly observable indices of opioid withdrawal in rhesus monkeys

Some monoamine uptake inhibitors (e.g., cocaine) attenuate the subjective and discriminative stimulus effects of opioid withdrawal. This study examined a role for dopamine transporters and receptors as targets for drugs to modify the discriminative stimulus effects of opioid withdrawal and further examined a subset of these drugs for their capacity to modify some directly observable and physiologic indices of withdrawal. Rhesus monkeys receiving 2 mg/kg/day of L: -alpha-acetylmethadol discriminated the opioid antagonist naltrexone (0.0178 mg/kg s.c.). The naltrexone discriminative stimulus was attenuated not only by the mu agonist morphine but also by the dopamine D(2)-like receptor agonists bromocryptine and quinpirole. In contrast, the naltrexone discriminative stimulus was not consistently modified by the non-selective, D(1)- and D(2)-like agonist apomorphine or by uptake inhibitors with high selectivity for dopamine transporters (GBR 12909, RTI 113, and RTI 177). In the same monkeys, naltrexone dose dependently decreased body temperature, increased breathing frequency, and induced directly observable signs (grimacing, salivation, and unusual posture). Hypothermia, hyperventilation, and signs of withdrawal were significantly attenuated by morphine and not by quinpirole. Attenuation of opioid withdrawal by D(2)-like receptor agonists that have lower efficacy than dopamine, and not by uptake inhibitors with selectivity for dopamine transporters, suggests that magnitude of receptor stimulation (e.g., efficacy) and selectivity at dopamine receptors are important factors in the modulation of opioid withdrawal. Attenuation of the naltrexone discriminative stimulus by drugs that inhibit both dopamine and serotonin uptake (e.g., cocaine) could result from an inhibitory effect of serotonin on dopamine. The role of dopamine in opioid withdrawal appears to be restricted to subjective (i.e., not somatic) indices [corrected]

Inhibitory effect of 5-hydroxytryptamine on hyperphagia in mice with genetic overexpression of neuropeptide Y

The present study examined the effect of 5-hydroxytraptamine (5-HT) on the feeding behavior of transgenic mice with neuropeptide Y (NPY) overexpression. Solution of 5-HT (1, 2.5 or 5 mg/kg) was administered intraperitoneally into (1) NPY-overexpressing mice, and (2) wild-type mice with 2-deoxy- d-glucose (2-DG) induced hyperphagia. The NPY-overexpressing mice were further divided into five groups: (1) control mice, (2) mice treated with 5-HT (5 mg/kg), (3) mice treated with 5-HT (5 mg/kg) and ketanserin (0.5 or 1 mg/kg), a 5-HT 2A receptor antagonist, (4) mice treated with insulin (1 IU/kg), and (5) mice treated with insulin (1 IU/kg) and 5-HT (5 mg/kg). Food intake and plasma glucose levels were measured. The results showed that 5-HT reduced hyperphagia in both NPY-overexpressing mice and 2-DG-treated mice in dose-dependent manner. Hyperglycemia was induced by 5-HT administration. Ketanserin antagonized the 5-HT induced hypophagia and hyperglycemia. Insulin, on the other hand, prevented 5-HT induced hyperglycemia but not the hypophagic effect. In conclusion, 5-HT reduces hyperphagia in the NPY-overexpressing rat through action on 5-HT 2A receptors and this hypophagic effect of 5-HT does not depend on the hyperglycemia.

Spinal anti-nociceptive effect of calcitonin in an osteoporotic model rat--functional recovery of descending serotonergic inhibition

Although calcitonin is generally used to relieve chronic pain accompanying osteoporosis, little is known about what kind of noxious sensation is alleviated by calcitonin. We examined actions of calcitonin on nociceptive transmission in the spinal dorsal horn of ovariectomized (OVX) rats using in vivo patch-clamp technique. Inhibitory effect of serotonin on mechanical noxious inputs to dorsal horn neurons was reduced in OVX rats. This mechanical hyperalgesia observation in OVX rats was attenuated by calcitonin treatment.

Paradoxical Inhibitory Effect of Serotonin on Cortisol Production from Adrenocortical Lesions Causing Cushing's Syndrome

In the human adrenal gland, serotonin (5‐HT) stimulates cortisol production through a paracrine mechanism involving 5‐HT4 receptors positively‐coupled to adenylyl cyclase. A hyperresponsiveness of adrenocortical tissue to 5‐HT has also been described in several cases of ACTH‐independent bilateral macronodular adrenal hyperplasias (AIMAHs) and adenomas causing Cushing's syndrome. In the present study, we report two cases of cortisol‐producing adrenocortical lesions, i.e. one AIMAH (case 1) and one adenoma (case 2), whose secretory activity was inhibited in vitro by 5‐HT. The potencies (pIC50) and efficacies (Emax) of 5‐HT to inhibit cortisol secretion were 8.2 ± 0.4 and − 64.1% ± 7.5% in case 1, and 9.2 ± 0.5 and − 32.3% ± 3.8% in case 2. The specific 5‐HT4 antagonist GR 113808 failed to influence the 5‐HT‐induced decrease in cortisol production by the two tissues, indicating that the paradoxical inhibitory effect of 5‐HT could not be accounted for by activation of eutopic 5‐HT4 receptors. These results suggest that the tissues expressed aberrant 5‐HT receptors. In conclusion, the present study provides the first evidence for an inhibitory effect of 5‐HT on cortisol secretion in adrenocortical lesions causing Cushing's syndrome. Our data also suggest that expression of illegitimate membrane receptors by cortisol‐producing adrenal hyperplasias and/or adenomas may convert a paracrine stimulatory factor into an inhibitory signal.