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)

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

Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families (5-HT1-5-HT7). With the exception of the 5-HT3 which is a ligand-gated ion channel, all others are G-protein coupled receptors with each family sharing structural, pharmacological and transductional characteristics. 5-HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission, and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache. In this respect, activation of vascular 5-HT2B and/or 5-HT7 receptors, possibly as a consequence of the sudden rise in 5-HT levels reported at the onset of a migraine attack, would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents, hence initiating the manifestation of head pain. At this stage in the migraine process, activation of specific subtypes of 5-HT1 receptors has proven clinically effective in relieving migraine pain. Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally. In contrast, activation of vascular 5-HT1B receptors would constrict meningeal vessels hence recovering their pre-migraine diameter. The recent availability of subtype selective 5-HT1D and 5-HT1F receptor agonists should allow a further test of the neural/vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile.
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PMID:The biology of serotonin receptors: focus on migraine pathophysiology and treatment. 1056 26

Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity.
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PMID:Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. 1129 43

Recently, a series of 5-HT7 receptor antagonists have been developed (24,29,36,68). Among them SB-258741, R-(+)-1-(toluene-3-sulfonyl)-2-[2-(4-methylpiperidin-1-yl)ethyl]-pyrrolidine, (compound "13" in 36,37) was one of the most potent and specific compounds. Due to a lack of specific ligands the pharmacology of 5-HT7 receptor antagonists is still relatively unexplored. It has been suggested, however, that 5-HT7 receptor ligands could be useful in the therapy of various disorders such as sleep disorders, schizophrenia, depression, migraine, epilepsy, pain, or memory impairment. Many of these conceivable indications are not supported by pharmacological data. It is, therefore, of particular interest to review the data generated from studies of one of these most potent and specific 5-HT7 receptor antagonists, SB-258741, with a goal of testing the validity of the proposed clinical indications. In this review, the author describes pharmacology of this compound in order to define its potential clinical use. The available safety pharmacology data are discussed in an attempt to predict potential side effects of specific 5-HT7 receptor antagonists.
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PMID:SB-258741: a 5-HT7 receptor antagonist of potential clinical interest. 1207 May 28

The antinociceptive effects of the serotonin (5-HT)1A/7 receptor agonist 8-hydroxy-dipropylaminotetralin (8-OH-DPAT) administered into the medial thalamus were evaluated. Pain behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization after discharges, VADs) levels of the neuraxis were elicited by tailshock. Administration of 8-OH-DPAT (5, 10, and 20 microg/side) into nucleus parafascicularis (nPf) produced dose-dependent increases in VDS and VAD thresholds, but failed to elevate SMR threshold. The increase in VAD threshold was significantly greater than that of VDS threshold. Similar effects were observed with administration of 8-OH-DPAT (20 microg/side) into the rostral portion of the central lateral thalamic nucleus. The bilateral or unilateral administration of 8-OH-DPAT (20 microg) into other thalamic nuclei, or into sites dorsal to nPf, did not elevate vocalization thresholds. Increases in vocalization thresholds produced by nPf-administered 8-OH-DPAT were mediated by both 5-HT1A and 5-HT7 receptors. Intra-nPf administration of the 5-HT1A receptor antagonist WAY-100635 (0.05 or 0.5 microg/side), or the 5-HT7 receptor antagonist SB-269970 (1 or 2 microg/side), but not the dopamine D2 receptor antagonist raclopride (10 microg/side), reversed 8-OH-DPAT induced elevations in vocalization thresholds. These results provide the first reported evidence of behavioral antinociception following the administration of a 5-HT agonist into the medial thalamus.
Pain 2005 Feb
PMID:Activation of 5-HT1A and 5-HT7 receptors in the parafascicular nucleus suppresses the affective reaction of rats to noxious stimulation. 1566 50

Several lines of evidence indicate that 5-HT7 receptors are involved in pain control at the level of the spinal cord, although their mechanism of action is poorly understood. To provide a morphological basis for understanding the action of 5-HT on this receptor, we performed an immunocytochemical study of 5-HT7 receptor distribution at the lumbar level. 5-HT7 immunolabelling is localized mainly in the two superficial laminae of the dorsal horn and in small and medium-sized dorsal root ganglion cells, which is consistent with a predominant role in nociception. In addition, moderate labelling is found in the lumbar dorsolateral nucleus (Onuf's nucleus), suggesting involvement in the control of pelvic floor muscles. Electron microscopic examination of the dorsal horn revealed three main localizations: 1) a postsynaptic localization on peptidergic cell bodies in laminae I-III and in numerous dendrites; 2) a presynaptic localization on unmyelinated and thin myelinated peptidergic fibers (two types of axon terminals are observed, large ones, presumably of primary afferent origin, and smaller ones partially from intrinsic cells; this presynaptic labelling represents 60% and 22% of total labelling in laminae I and II, respectively); and 3) 16.9% of labelling in lamina I and 19.8% in lamina II are observed in astrocytes. Labeled astrocytes are either intermingled with neuronal elements or make astrocytic "feet" on blood vessels. In dendrites, the labelling is localized on synaptic differentiations, suggesting that 5-HT may act synaptically on the 5-HT7 receptor. This localization is compared with other 5-HT receptor localizations, and their physiological consequences are discussed.
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PMID:Pre- and postsynaptic localization of the 5-HT7 receptor in rat dorsal spinal cord: immunocytochemical evidence. 1608 81

The possible pronociceptive role of peripheral and spinal 5-HT7 receptors in the formalin test was assessed. Local administration of 5-HT7 (SB-269970, 2.5-77.1 nmol/paw), but not 5-HT(1A) (WAY-100635, 1-60 nmol/paw), receptor antagonist significantly reduced formalin-induced flinching. Local 5-hydroxytryptamine (5-HT, 3-100 nmol/paw) or 5-carboxamidotryptamine (5-CT, 0.3-3 nmol/paw) (a 5-HT7/1A receptor agonist) augmented, in a dose-dependent manner, 0.5% formalin-induced nociceptive behavior. The local pronociceptive effect of 5-HT or 5-CT was significantly reduced by SB-269970 (25 and 77.1 nmol/paw), but not by WAY-100635 (10 nmol/paw). 5-HT7 receptors were observed in myelinated and unmyelinated axons of the digital nerves in rat hindpaw. Intrathecal SB-269970 (2.5-77.1 nmol/rat) or WAY-100635 (1-50 nmol/rat) did not modify 1% formalin-induced nociceptive behavior. Spinal 5-HT (25-200 nmol/rat) significantly reduced formalin-induced flinching behavior during phase 2. At lower doses (0.1-3 nmol/rat) intrathecal 5-CT dose-dependently increased flinching during phase 2. In contrast, higher doses (10-30 nmol/rat) of 5-CT reduced formalin-induced nociceptive behavior during both phases. The spinal pronociceptive effect of 5-CT was reduced by SB-269970 (7.7-77 nmol/rat), but not by WAY-100635 (10 nmol/rat). In addition, the spinal antinociceptive effect of 5-CT was partially reversed by WAY-100635 (10 nmol/rat). The spinal antinociceptive effect of 5-HT was unaffected either by SB-269970 (77 nmol/rat) or WAY-100635 (10 nmol/rat). Data suggest that 5-HT7, but not 5-HT1A, receptors play a pronociceptive role in peripheral and spinal sites in the rat formalin test.
Pain 2005 Sep
PMID:Pronociceptive role of peripheral and spinal 5-HT7 receptors in the formalin test. 1609 71

Neuropathic pain is generally resistant to "classical" analgesic drugs, including opioids, and there is still an urgent need for really effective treatments to alleviate pain caused by lesions of the peripheral and/or central nervous system. The pathophysiological mechanisms underlying neuropathic pain are still poorly known, and treatments are mainly empirical. Antidepressant drugs are generally prescribed first, with positive but limited results in a significant proportion of patients. Anticonvulsant drugs (carbamazepine, phenytoin, lamotrigine) are also used but are often poorly tolerated. Clinical studies and preclinical investigations support the idea that the nature of neuropathic pain, and the underlying mechanisms, are different in the cephalic (trigeminal) territories and the extracephalic (spinal) territories. In order to further investigate these regional differences, we used rat nerve ligature models. Comparison of allodynia/hyperalgesia in the vibrissal territory caused by unilateral ligature of the infraorbital nerve (2nd branch of the trigeminal nerve) with those in the hindpaw ipsilateral to unilateral ligature of the sciatic nerve revealed marked differences in their responses to sodium channel blockers (such as tetrodotoxin), serotonin (5-HT) receptor agonists and calcitonin gene-related peptide (CGRP) receptor antagonists. In particular, 5-HT7 receptor agonists were particularly effective at reducing allodynia in sciatic nerve-ligated rats, but were completely ineffective in infraorbital nerve-ligated rats. Conversely, triptans (5-HT1B/1D receptor agonists) and CGRP-receptor antagonists markedly inhibited cephalic allodynia in infraorbital nerve-ligated rats but failed to relieve neuropathic pain in sciatic nerve-ligated animals. Interestingly, ligature-induced expression of the proinflammatory cytokine interleukin-6 in central tissues showed marked differences in sciatic nerve- and infraorbital nerve-ligated rats, providing direct evidence of differences in the mechanisms underlying extra-cephalic- and cephalic neuropathic pain. Such preclinical studies should contribute to the design of innovative strategies for more effective and well-tolerated treatments for neuropathic pain in cephalic and extra-cephalic territories.
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PMID:[Neuropathic pain. Physiopathological mechanisms and therapeutic perspectives]. 1923 82

The rostroventromedial medulla (RVM) is an important source of descending modulatory systems that both inhibit and facilitate pain at the level of the spinal cord. Noxious stimuli can activate serotonergic neurons in the RVM and accelerate the turnover of 5-HT in the spinal cord. While numerous studies suggest a bidirectional role for serotonergic transmission at the spinal level, the subtypes of the 5-HT receptors that are associated with descending facilitation or inhibition have not been clearly determined. Here, we explore the relative contribution of spinal 5-HT7 and 5-HT3 receptors to antinociception or hyperalgesia associated with states of enhanced net descending inhibition or facilitation from the RVM. In uninjured rats, RVM microinjection of morphine produced dose-dependent antinociception in the noxious thermal paw flick test while RVM microinjection of CCK produced thermal hyperalgesia and tactile allodynia. Spinal administration of the 5-HT7 antagonist SB-269970, but not of the 5-HT3 antagonist ondansetron, blocked the antinociceptive effects of RVM morphine. In contrast, hyperalgesia induced by RVM-CCK was blocked by spinal ondansetron, but not by SB-269970. The antinociceptive effects of systemic morphine were also blocked by spinal SB-269970 but not ondansetron while hyperalgesia and allodynia resulting from SNL injury were blocked by spinal ondansetron, but not SB-269970. These studies suggest that descending pain inhibitory or facilitatory pathways from RVM act ultimately in the spinal cord in acute and chronic pain states through activation of 5-HT7 and 5-HT3 receptors, respectively.
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PMID:Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors. 1942 39


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