Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Hydroxytryptamine (5-HT) is known to act in peripheral tissues to produce pain and inflammation, yet the mechanisms underlying 5-HT-induced inflammation have not been well studied. The present study uses a rat knee joint model of inflammation (synovial plasma extravasation) and molecular biological techniques to determine the site of action of 5-HT and the specific 5-HT receptor subtype mediating synovial 5-HT-induced plasma extravasation. 5-HT (1 microM) stimulates synovial plasma extravasation 7-fold above base-line levels. Surgical lumbar sympathectomy, but not C-fiber depletion by neonatal capsaicin, dramatically reduces 5-HT-induced synovial plasma extravasation (P < .001), indicating that sympathetic efferents mediate this effect. Polymerase chain reaction amplification of 5-HT receptor cDNA demonstrates that 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A and 5-HT3, but not the 5-HT2C, receptor subtypes are present in lumbar sympathetic ganglia. With selective ligands for these receptor subtypes, we demonstrate that 5-HT-induced synovial plasma extravasation is mediated via the 5-HT2A receptor. These findings suggest a role for 5-HT2A antagonists in various synovial inflammatory pain states.
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PMID:5-Hydroxytryptamine-induced synovial plasma extravasation is mediated via 5-hydroxytryptamine2A receptors on sympathetic efferent terminals. 756 92

1. Selective antagonism of 5-HT4 receptors may provide therapeutic benefit in certain disorders of the myocardium, alimentary and lower urinary tract. We now report on RS 39604, a novel and selective 5-HT4 receptor antagonist and compare its pharmacological properties with those of SB 204070. 2. In guinea-pig striatal membranes, both RS 39604 and SB 204070 inhibited specific binding of [3H]-GR 113808 in a concentration-dependent manner yielding pKi estimates of 9.1 and 10.9, respectively. RS 39604 displayed a low affinity (pKi < 6.5) for 5-HT1A, 5-HT2C, 5-HT3, alpha 1c, D1, D2, M1, M2, AT1, B1 and opioid mu receptors and moderate affinity for sigma 1, (pKi = 6.8) and sigma 2 (pKi = 7.8) sites. 3. In the rat isolated oesophagus, precontracted with carbachol, RS 39604 (30-300 nM) behaved as a competitive antagonist towards 5-HT-induced relaxation (pA2 = 9.3; Schild slope = 1.0). We and others have shown previously that SB 204070 behaves as an unsurmountable antagonist in this preparation (pA2 approximately 10.5). In the guinea-pig isolated ileal mucosa, RS 39604 (30 nM) antagonized 5-MeOT-induced increase in short-circuit current (pA2 = 9.1). 4. In anaesthetized vagotomized micropigs, RS 39604, administered by the i.v. or intraduodenal (i.duod.) route, produced dose-dependent inhibition of 5-HT-induced tachycardia (ID50 = 4.7 micrograms kg-1, i.v. and 254.5 micrograms kg-1, i.duod). At maximal doses of 30 micrograms kg-1, i.v. and 6 mg kg-1, i.duod., the inhibitory effects of RS 39604 lasted for more than 6 h. In this preparation, SB 204070 was as potent as RS 39604by the i.v. route but was inactive by the intraduodenal route at doses up to 3 mg kg-1.5. In conscious mice, RS 39604, administered by the i.p. or p.o. route, produced dose-depend entinhibition of 5-hydroxytryptophan (5-HTP)-induced diarrhoea (ID50= 81.3 microg kg-1, i.p. and 1.1 mg kg-1,p.o.). In this assay, SB 204070 was inactive by the oral route at doses up to 30 mg kg-1.6. In anaesthetized guinea-pigs, RS 39604 antagonized the contractile effect of 5-HT in the proximal colon by producing parallel, dextral displacement of the dose-response curve to 5-HT. The mean dose ratios to 5-HT at 0.1 mg kg-1, i.v., 1 mg kg-1, i.v. and 10 mg kg-1, i.duod. were 4.6, 30.7 and 10.8,respectively. SB 204070 behaved as an unsurmountable antagonist in this assay.7. In a model of visceral pain in conscious rats, RS 39604 (0.01-1 mg kg-1, i.v.) did not affect colorectal distension-induced increases in arterial pressure whereas morphine (1 mg kg-1, i.v.) produced significant inhibition of the response, implying that 5-HT4 receptors are not involved in nociception in this model.8. The data suggest that RS 39604 is a high affinity and selective 5-HT4 receptor antagonist that is orally active and long-lasting in vivo. It is concluded that RS 39604 may be the preferable probe to use for investigating the physiological and pathophysiological role of 5-HT4 receptors in vivo.
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PMID:RS 39604: a potent, selective and orally active 5-HT4 receptor antagonist. 758 7

The evidence for an involvement of 5-hydroxytryptamine (5-HT) and nitric oxide (NO) in the initiation of migraine is reviewed. Based on this, the following scenario is proposed. Endogenous 5-HT, arising perhaps from platelets but more likely from perivascular 5-HT-containing neurons in response to different types of "stress", would activate 5-HT2B/5-HT2C receptors on endothelial cells of the cerebral vasculature to release NO. Nitric oxide would, by directly activating sensory neurons, induce neurotransmitter release, plasma extravasation, pain and hyperalgesia. The result would be induction of the "sterile" inflammatory response, believed to be the key step in the development of migraine.
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PMID:The 5-hydroxytryptamine-nitric oxide connection: the key link in the initiation of migraine? 763 13

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.
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PMID:Role of 5-HT in stress, anxiety, and depression. 872 50

While serotonin has been shown to play an important role in peripheral pain mechanisms, the specific subtypes of receptors involved and their differential distribution between the sensory and sympathetic nervous system remains poorly understood. In this study, the presence of messenger RNA for rat serotonin receptor subtypes in peripheral sensory and sympathetic ganglia was detected using the method of polymerase chain reaction. Lumbar dorsal root ganglia, superior cervical sympathetic ganglia and lumbar sympathetic ganglia were excised from anesthetized Sprague-Dawley rats. Oligonucleotide primers were chosen based on unique regions of complementary DNA sequence for each of the 12 cloned rat serotonin receptor subtypes (i.e. 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT5B, 5-HT6 and 5-HT7) and high stringency conditions were used during polymerase chain reaction. Within lumbar dorsal root ganglia, the presence of the 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2C, 5-HT3 and 5-HT7 receptor subtype messenger RNAs was detected. Within superior cervical ganglia, the presence of messenger RNA for 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT3, 5-HT6, and 5-HT7 receptor subtypes was detected. Lumbar sympathetic ganglia displayed banding identical to the superior cervical ganglia with the exception of the 5-HT6 receptor which was not detected in the lumbar sympathetic ganglia. The polymerase chain reaction product from each positively-detected receptor subtype was subcloned and sequenced and found to correspond to published complementary DNA sequences. Findings from this study may direct further efforts to determine the role of 5-hydroxytryptamine receptors in the peripheral nervous system.
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PMID:5-Hydroxytryptamine receptor subtype messenger RNAs in rat peripheral sensory and sympathetic ganglia: a polymerase chain reaction study. 884 58

Although serotonin has been shown to play an important role in peripheral pain mechanisms, the specific subtypes of serotonin receptors involved in pain and hyperalgesia remain poorly understood. To date, no previous study has attempted to determine the presence of any serotonin receptor subtype in human dorsal root ganglia. In this study, the presence of messenger RNA for eight human serotonin receptor subtypes in lumbar dorsal root ganglia was detected using the method of polymerase chain reaction. Dorsal root ganglia were excised post mortem from four patients. Oligonucleotide primers were chosen based on unique regions of complimentary DNA sequence for eight cloned human serotonin receptor subtypes (i.e. 5-HT1A, 5-HT1D alpha, 5-HT1D beta, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2C and 5-HT7). The presence of 5-HT1D alpha, 5-HT1D beta, 5-HT1E, 5-HT1F, 5-HT2A and 5-HT7 receptor subtype messenger RNA was detected in dorsal root ganglia from three of the four subjects. 5-HT1A receptor subtype messenger RNA was detected in one of the four subjects. No 5-HT2C receptor subtype messenger RNA could be detected. Findings from this study may direct further efforts to determine the role of serotonin receptors in the peripheral nervous system.
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PMID:5-Hydroxytryptamine receptor subtype messenger RNAs in human dorsal root ganglia: a polymerase chain reaction study. 931 30

Involvement of the cerebral serotoninergic system has been invoked to explain the origin of the pain and the vascular phenomena in migraine. To further investigate the type of cerebral serotonin receptors that may be altered in migraine, the prolactin (PRL) and cortisol responses to m-chlorophenylpiperazine (mCPP), a selective 5-HT1A,-5-HT(2A/C) receptor agonist, were monitored in 12 patients suffering from migraine without aura and in 14 matched healthy controls. Each subject underwent two challenges, one with mCPP (0.5 mg/kg) and the other with placebo (orally) using a double-blind crossover design. Anxiety level was measured by the State Trait Anxiety Inventory. Migraine patients had a greater PRL response to mCPP (p = 0.05) and greater anxiety (p < 0.01) than controls; cortisol response to mCPP did not differ suggesting that 5-HT2C receptors are normal in migraine. Augmented PRL response to mCPP could derive from 5-HT1A receptor hypersensitivity, perhaps as as a consequence of anxiety due to pain expectation. Cerebral 5-HT1A hypersensitivity could also explain the increased occurrence of migraine attacks during anxiety.
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PMID:5-HT1A receptor hypersensitivity in migraine is suggested by the m-chlorophenylpiperazine test. 972 41

Recently, there has been a growing interest in long-term consequences of neonatal pain because modern neonatal intensive care units routinely employ procedures that cause considerable pain and may be followed by local inflammation and hyperalgesia lasting for several hours or even days. To address this question, we developed a rat model of short lasting (<2 days) early local inflammatory insult produced by a single injection of 0.25% carrageenan (CAR) into the plantar surface of a hindpaw. Previously, we demonstrated that rats receiving this treatment within the first week after birth grow into adults with a global reduction in responsiveness to acute pain. Here, we report that these animals also manifest a low anxiety trait associated with reduced emotional responsiveness to stress. This conclusion is based in the following observations: (a) rats in our model display reduced anxiety on an elevated plus-maze; (b) in the forced swim test, these rats exhibit behavioral characteristics associated with stronger ability for stress coping; and (c) these animals have reduced basal and stress-induced plasma levels of such stress-related neuroendocrine markers as corticotropin-releasing factor, vasopressin, and adrenocorticotrophic hormone. In addition, we used DNA microarray and real-time reverse-transcriptase polymerase chain reaction to profile long-term changes in gene expression in the midbrain periaqueductal gray (PAG; a region involved in both stress and pain modulation) in our animal model. Among the affected genes, serotonergic receptors were particularly well represented. Specifically, we detected increase in the expression of 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C and 5-HT4 receptors. Several of these receptors are known to be involved in the anxiolytic and analgesic activity of the PAG. Finally, to determine whether neonatal inflammatory insult induces elevation in maternal care, which may play a role in generating long-term behavioral alterations seen in our model, we examined maternal behavior for 3 days following CAR injection. Indeed, we observed a substantial increase in maternal attention to the pups at the time of inflammation, but this increase was not without its cost: a period of significant maternal neglect afterward.
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PMID:Alterations in stress-associated behaviors and neurochemical markers in adult rats after neonatal short-lasting local inflammatory insult. 1573 Aug 69

The serotonin (5-hydroxytryptamine) 5-HT2 receptor subfamily consists of three members, 5-HT2A, 5-HT2B, and 5-HT2C. These receptors share high homology in their amino acid sequence, have similar signaling pathways, and have been indicated to play important roles in feeding, anxiety, aggression, sexual behavior, mood, and pain. Subtype-selective agonists and antagonists have been explored as drugs for hypertension, Parkinson's disease, sleep disorders, anxiety, depression, schizophrenia, and obesity. In this study, we report the development of homogeneous agonist binding assays in a scintillation proximity assay (SPA) format to determine the high-affinity binding state of agonist compounds for the human 5-HT2C, 5-HT2A, and 5-HT2B receptors. The 5-HT2 agonist 1-(4- [125I]iodo-2,5-dimethoxyphenyl)-2-aminopropane ([125I]DOI) was used to label the high-affinity sites for the 5-HT2A and 5-HT2C receptors. The high-affinity sites for the 5-HT2B receptor were labeled with [3H]lysergic acid diethylamide. Total receptor expression was determined with the 5-HT2 antagonist [3H]mesulergine for the 5-HT2B and 5-HT2C receptors, and [3H]ketanserin for the 5-HT2A receptor. The agonist high-affinity binding sites accounted for 2.3% (5-HT(2C) receptor), 4.0% (5-HT2A receptor), and 22% (5-HT2B receptor) of the total receptor population. Competition binding studies using known agonists indicated high Z' values of the agonist binding assays in SPA format (Z' > 0.70). The Ki values of 5-HT, (R)(-)DOI, and VER-3323 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors by SPA format were equivalent to published data determined by filtration binding assays. These results indicate that agonist binding assays in SPA format can be easily adapted to a high throughput assay to screen for selective 5-HT2C receptor agonists, as well as for selectivity profiling of the compounds.
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PMID:Development of homogeneous high-affinity agonist binding assays for 5-HT2 receptor subtypes. 1643 60

There is an association between depression and chronic pain, and some antidepressants exert antinociceptive effects in humans and laboratory animals. We examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, on mechanical allodynia and its mechanism of action in the mouse chronic pain model, which was prepared by partially ligating the sciatic nerve. The antiallodynic effect was measured using the von Frey test. Fluvoxamine produced antiallodynic effects following both systemic and intrathecal administration. In 5-hydroxytryptamine (5-HT)-depleted mice, prepared by intracerebroventricular injection of 5,7-dihyroxytryptamine, the fluvoxamine-induced antiallodynic effect was significantly attenuated. The antiallodynic effects of systemic fluvoxamine were also reduced by both systemic and intrathecal administration of ketanserin, a 5-HT2A/2C receptor antagonist. In addition, fluvoxamine also induced antinociceptive effect in the acute paw pressure test, and this effect was antagonized by the 5-HT3 receptor antagonist granisetron. These results indicate that fluvoxamine exerts its antiallodynic effects on neuropathic pain via descending 5-HT fibers and spinal 5-HT2A or 5-HT2C receptors, and the antinociception on acute mechanical pain via 5-HT3 receptors.
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PMID:Fluvoxamine, a selective serotonin reuptake inhibitor, exerts its antiallodynic effects on neuropathic pain in mice via 5-HT2A/2C receptors. 1684 19


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