A large body of research including animal and human studies has confirmed the crucial role of the serotonin (5-HT) system in the regulation of nociception and chronic pain-related behaviors. In recent years, the functional status of the 5-HT system in descending inhibition and facilitation of spinal nociceptive processing has been reevaluated by novel genetic manipulation techniques and selective agents for 5-HT receptor subtypes. Although these studies shed more light on several aspects of descending 5-HT and spinal 5-HT receptors functioning in descending modulation in pain perception, the current knowledge about the specific role of descending 5-HT system in the induction and maintenance of persistent pain remains fragmentary. In this paper, we review the available data from recent studies of the inhibitory or facilitatory influence from descending 5-HT-spinal 5-HT receptor system in acute and persistent pain, attempt to dissect the involvement of this signaling pathway in neural circuits of maintenance of persistent pain and discuss some issues that need to be considered for further pain research.
Animals ; Humans ; Pain ; physiopathology ; Receptors, Serotonin ; physiology ; Serotonin ; physiology

Melittin-induced tonic pain model is characterized by local inflammation, edema, spontaneous flinchings, and sustained mechanical hypersensitivity. These nociceptive responses are mediated through selective activation of capsaicin-sensitive primary afferent fibers by melittin. The present study was undertaken to elucidate the role of peripheral 5-hydroxytryptamine (5-HT) receptors in the melittin-induced nociceptive responses. Changes in mechanical threshold, flinching behaviors and paw thickness were measured in rat intraplantarly injected with melittin (40microgram/paw) alone or treated together with melittin and 5-HT receptor antagonists. WAY-100635 (100microgram & 200microgram/paw), isamoltane hemifumarate (100microgram & 200microgram/paw), methysergide maleate (60microgram, 120microgram & 200microgram/paw) and ICS-205,930 (100microgram & 200microgram/paw) were intraplantarly injected 20 min before melittin injection. All 5-HT receptor antagonists tested in this experiment significantly attenuated the ability of melittin to reduce mechanical threshold and to induce flinching behaviors. 5-HT receptor antagonists, except ICS-205,930, had mild inhibitory effect on melittin-induced edema. These experimental findings suggest that multiple peripheral 5-HT receptors are involved in the melittin-induced nociceptive responses.
Animals ; Edema ; Hypersensitivity ; Inflammation ; Melitten ; Methysergide ; Rats* ; Receptors, Serotonin ; Serotonin*

Lamotrigine is an antiepileptic drug widely used to treat epileptic seizures. Using whole-cell voltage clamp recordings in combination with a fast drug application approach, we investigated the effects of lamotrigine on 5-hydroxytryptamine (5-HT)₃ receptors in NCB-20 neuroblastoma cells. Co-application of lamotrigine (1~300 µM) resulted in a concentration-dependent reduction in peak amplitude of currents induced by 3 µM of 5-HT for an IC₅₀ value of 28.2±3.6 µM with a Hill coefficient of 1.2±0.1. These peak amplitude decreases were accompanied by the rise slope reduction. In addition, 5-HT₃-mediated currents evoked by 1 mM dopamine, a partial 5-HT₃ receptor agonist, were inhibited by lamotrigine co-application. The EC₅₀ of 5-HT for 5-HT₃ receptor currents were shifted to the right by co-application of lamotrigine without a significant change of maximal effect. Currents activated by 5-HT and lamotrigine co-application in the presence of 1 min pretreatment of lamotrigine were similar to those activated by 5-HT and lamotrigine co-application alone. Moreover, subsequent application of lamotrigine in the presence of 5-HT and 5-hydroxyindole, known to attenuate 5-HT₃ receptor desensitization, inhibited 5-HT₃ receptor currents in a concentration-dependent manner. The deactivation of 5-HT₃ receptor was delayed by washing with an external solution containing lamotrigine. Lamotrigine accelerated the desensitization process of 5-HT₃ receptors. There was no voltage-dependency in the inhibitory effects of lamotrigine on the 5-HT3 receptor currents. These results indicate that lamotrigine inhibits 5-HT₃-activated currents in a competitive manner by binding to the open state of the channels and blocking channel activation or accelerating receptor desensitization.
Dopamine ; Epilepsy ; Neuroblastoma* ; Receptors, Serotonin, 5-HT3 ; Serotonin

5-Hydroxytryptamine (5-HT) type 3 receptor (5-HT₃R) is the only type of ligand-gated ion channel in the 5-HT receptor family. Through the high permeability of Na⁺, K⁺, and Ca²⁺ and activation of subsequent voltage-gated calcium channels (VGCCs), 5-HT₃R induces a rapid increase of neuronal excitability or the release of neurotransmitters from axon terminals in the central nervous system (CNS). 5-HT₃Rs are widely expressed in the medial prefrontal cortex (mPFC), amygdala (AMYG), hippocampus (HIP), periaqueductal gray (PAG), and other brain regions closely associated with anxiety reactions. They have a bidirectional regulatory effect on anxiety reactions by acting on different types of cells in different brain regions. 5-HT₃Rs mediate the activation of the cholecystokinin (CCK) system in the AMYG, and the γ‍-aminobutyric acid (GABA) "disinhibition" mechanism in the prelimbic area of the mPFC promotes anxiety by the activation of GABAergic intermediate inhibitory neurons (IINs). In contrast, a 5-HT₃R-induced GABA "disinhibition" mechanism in the infralimbic area of the mPFC and the ventral HIP produces anxiolytic effects. 5-HT₂R-mediated regulation of anxiety reactions are also activated by 5-HT₃R-activated 5-HT release in the HIP and PAG. This provides a theoretical basis for the treatment of anxiety disorders or the production of anxiolytic drugs by targeting 5-HT₃Rs. However, given the circuit specific modulation of 5-HT₃Rs on emotion, systemic use of 5-HT₃R agonism or antagonism alone seems unlikely to remedy anxiety, which deeply hinders the current clinical application of 5-HT₃R drugs. Therefore, the exploitation of circuit targeting methods or a combined drug strategy might be a useful developmental approach in the future.
Serotonin ; Receptors, Serotonin, 5-HT3 ; Anxiety ; Neurons ; gamma-Aminobutyric Acid

Selective serotonin reuptake inhibitors (SSRIs) are currently the treatment of choice in depression and constitute major portion of prescription in depressive patients. The role of serotonin receptors in bone is emerging, raising certain questions regarding the effect of blockade of serotonin reuptake in the bone metabolism. Clinical studies have reported an association of SSRI antidepressants which with increase in fracture and decrease in bone mineral density. This review focus on recent evidence that evaluate the association of SSRIs with the risk of fracture and bone mineral density and also the probable mechanisms that might be involved in such effects.
Antidepressive Agents ; Bone Density ; Depression ; Humans ; Metabolism ; Prescriptions ; Receptors, Serotonin ; Serotonin Uptake Inhibitors* ; Serotonin*

BACKGROUND: Spinal 5-hydroxytryptamine (5-HT) has been shown to display an antinociceptive effect, which is mediated by 5-HT receptors. Previous studies have revealed the presence of at least four types of 5-HT receptors in the spinal cord. The aim of this study was to assess the role of each spinal 5-HT receptor in the antinociception of intrathecal 5-HT using the formalin test. METHODS: Rats were implanted with lumbar intrathecal catheters. After the administration of 5-HT, formalin-induced nociceptive behavior (flinching response) was observed for 60 min. To further clarify the role of the 5-HT receptors in the antinociception of 5-HT, several antagonists of 5-HT receptors were administered intrathecally 10 min before 5-HT delivery, and formalin was injected 10 min later. RESULTS: Intrathecal 5-HT dose-dependently suppressed flinching during phase 1 and 2 in the formalin test. 5-HT1B (GR 55562), 5-HT2C (N-desmethylclozapine), 5-HT3 (LY-278,584) and 5-HT4 (SDZ-205,557) receptors antagonists reversed this antinociception by 5-HT during both phases in the formalin test. 5-HT1A receptor antagonist (WAY-100635) decreased antinociception by 5-HT in phase 2, but not in phase 1. A 5-HT1D receptor antagonist (BRL 15572) did not antagonize the antinociception of 5-HT in either phases. CONCLUSIONS: Spinal 5-HT1B, 5-HT2C, 5-HT3 and 5-HT4 receptors, but not the 5-HT1D receptor, are involved in the antinociception of serotonin in the facilitated state and in the acute pain evoked by a formalin stimulus. The 5-HT1A receptor seems to play a role in 5-HT-induced antinociception in the facilitated state.
Acute Pain ; Animals ; Catheters ; Formaldehyde ; Pain Measurement ; Rats* ; Receptor, Serotonin, 5-HT1A ; Receptor, Serotonin, 5-HT1D ; Receptors, Serotonin ; Receptors, Serotonin, 5-HT4 ; Serotonin* ; Spinal Cord*

A number of studies have demonstrated that 5-hydroxytryptamine (5-HT) can induce muscle contraction or relaxation response and enhance secretion in the gastrointestinal tract via a multiplicity of 5-HT receptor subtypes. In the present study, we investigated the pharmacological characterization of the 5-HT-induced contractile response in longitudinal smooth muscle isolated from the feline ileum. Addition of 5-HT into muscle chambers enhanced the basal tone and spontaneous activity in a concentration-dependent manner. The neurotoxin tetrodotoxin did not alter the 5-HT-induced contraction of the longitudinal muscles. Neither atropine nor guanethidine affected the contraction. The 5-HT agonists, 5-methylserotonin hydrochloride and mosapride, also evoked concentration-dependent contractions. The 5-HT-induced contraction was enhanced by the 5HT2 receptor antagonist ketanserin and the 5-HT3 receptor antagonist ondansetron but was inhibited by the 5-HT1 receptor antagonist methysergide and 5-HT4 receptor antagonist GR113808. These results indicate that 5-HT1 and 5-HT4 receptors may mediate the contraction of the 5-HT-induced response and 5-HT2 and 5-HT3 receptors may mediate 5-HT-induced relaxation in feline ileal longitudinal smooth muscles.
Atropine ; Benzamides ; Contracts ; Gastrointestinal Tract ; Guanethidine ; Ileum ; Indoles ; Ketanserin ; Methysergide ; Morpholines ; Muscle Contraction ; Muscle, Smooth ; Muscles ; Ondansetron ; Receptors, Serotonin ; Receptors, Serotonin, 5-HT1 ; Receptors, Serotonin, 5-HT3 ; Receptors, Serotonin, 5-HT4 ; Relaxation ; Serotonin ; Serotonin Receptor Agonists ; Sulfonamides ; Tetrodotoxin

5-hydroxtryptamine (5-HT, serotonin) has been recognized not only as a neurotransmitter and vasoactive agent, but also as a growth factor. 5-HT mainly binds to 5-HT(2) receptors or 5-HT(1) receptors on cell surface to stimulate cell proliferation through Ras or MAPK pathway in many cell types. It has been reported that 5-HT stimulates megakaryocytopoiesis via 5-HT receptors. The possible mechanism of 5-HT on the proliferation and differentiation of megakaryocytes (MK) has been discussed in this review article. In early stage of megakaryocytopoiesis, 5-HT may bind to 5-HT(2B) receptor on megakaryocytes, and promotes their proliferation and differentiation. In the late stage, 5-HT may involve in the platelet release procedure by inducing nitric oxide (NO) synthesis via 5-HT(2A) receptors. 5-HT can also antagonize the apoptotic effect induced by thrombospondin-1 (TSP-1) which is a platelet alpha granule protein and has synergic effect with platelet-derived growth factor (PDGF) to enhance megakaryocytes proliferation. Therefore, 5-HT is likely to be an important substance in the feedback regulation of thrombopoiesis. In this review the 5-HT and its receptors, 5-HT as cell growth factor, pathway of 5-HT stimulating cell proliferation and influance of 5-HT on MK-progenitor cells were summarized.
Humans ; Megakaryocytes ; physiology ; Receptors, Serotonin ; metabolism ; Receptors, Serotonin, 5-HT2 ; metabolism ; Serotonin ; metabolism ; pharmacology ; Thrombopoiesis ; physiology ; Thrombopoietin ; physiology

PURPOSE: The aim of this study was to assess the potential involvement of a specific subtype of 5-hydroxytryptamine (5-HT), 5HT(2) receptors in neurally-induced contractions of the human detrusor. METHODS: Contractile responses to electrical field stimulation (EFS) were examined in human isolated urinary bladder muscle strips. The potentiation of EFS-induced detrusor contraction was examined by adding cumulative concentrations of a 5-HT and 5-HT(2) receptor agonist, α-methyl-serotonin (α-Me-5-HT) (1nM–100μM) in the presence or absence of a 5-HT₂ antagonist, ketanserin (5-HT(2A)>5-HT(2C)) or naftopidil (5-HT(2B)>5-HT(2A)) (0.3–3μM). RESULTS: 5-HT and α-Me-5-HT potentiated EFS-induced contraction with a maximal effect (E(max)) of 37.6% and 38.6%, respectively, and with pEC(50) (negative logarithm of the concentration required for a half-maximal response to an agonist) values of 8.3 and 6.8, respectively. Neither ketanserin nor naftopidil at any concentration produced a rightward displacement of the α-Me-5-HT concentration response curve. Instead, the E(max) of α-Me-5-HT increased in the presence of ketanserin at 0.3–1μM and in the presence of naftopidil at 1μM to 51% and 56%, respectively, while the E(max) in the presence of vehicle alone was 36%. The highest concentration (3μM) of either drug, however, fully reversed the enhancement. CONCLUSIONS: The potentiating effect of α-Me-5-HT on neurally-induced contraction of human urinary bladder muscle strips was not found to be mediated via any 5-HT(2) receptor subtypes. The underlying mechanism for the enhancement of the α-Me-5-HT potentiating effect on detrusor contractility by ketanserin and naftopidil remains unknown; however, our results suggest that these drugs may be useful for treating contractile dysfunction of the detrusor, as manifested in conditions such as underactive bladder.
Humans* ; Ketanserin* ; Prostatism ; Receptors, Adrenergic, alpha-1 ; Receptors, Serotonin ; Serotonin ; Urinary Bladder Neck Obstruction ; Urinary Bladder*

The mechanism of serotonin(5-HT) induced contraction and Ca++ mobilization was investigated in right cut from rat aorta. Since it is known that 5-HT can interact with alpha-adrenoceptors in addition to a specific action on 5-HT receptors, the effects alpha-adrenoceptors antagonists on these contractile responses to 5-HT were investigated. The results are as follows : 1) 5-HT produced a strong transient contraction and a concentration dependent contraction. 2) The contractile tension to 5-HT increased with extracellular Ca++ concentration (0.1-5mM). 3) The response produced by rings exposed to Ca++-free PSS was significantly weaker than that produced by rings exposed to calcium containing PSS. When rings of aorta that had been stimulated with 5-HT once for 30 min in Ca++-free TBT were washed 4 times for at least; 20 min in zero Ca++PSS to remove 5-HT, than reexposed to 5-HT in Ca++-free TBT, a phasic contraction was not seen during the second stimulation with 5-HT. 4) The contractile response of 5-HT was inhibited by alpha-adrenergic receptor blocker, phenoxybenzamine and phentolamine. Phentolamine(10(-8)M) antagonized response to high concentrations of 5-HT but responses to low concentrations of 5-HT were not antagonized. 5) The contraction induced by 5-HT in Ca++-free PSS was investigated with phentolamin, methysergide. It was blocked by methysergide but not blocked by phentolamine. 6) These results suggest that 5-HT -induced contraction is the effect of both transmembrane Ca++ influx and the mobilization of intracellular Ca++. Low concentration of 5-HT act on specific 5-HT receptors but high concentration of 5-HT also act on alpha-adreno-receptors.
Animals ; Aorta* ; Calcium ; Methysergide ; Phenoxybenzamine ; Phentolamine ; Rats* ; Receptors, Adrenergic ; Receptors, Serotonin ; Serotonin