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)

A number of common diseases in humans, including gastroduodenal ulcer and irritable bowel syndrome, show circadian rhythms in pain and discomfort. The neurohormone melatonin is released from enterochromaffin cells in the intestinal mucosa and from the pineal gland but its role in gastrointestinal function is largely unknown. We have studied the involvement of melatonin in stimulation of the mucosa-protective alkaline secretion by the duodenal mucosa. A 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ in anesthetized rats and duodenal HCO3- secretion titrated by pH-stat. Duodenal close intra-arterial infusion of melatonin or the full agonist 2-iodo-N-butanoyl- 5-methoxytryptamine significantly increased the secretion and pretreatment with the melatonin (predominantly MT2-receptor specific) antagonist luzindole almost abolished the response. Intracerebroventricular (i.c.v.) infusion of the alpha1-adrenoceptor agonist phenylephrine (12.2 micromol kg(-1) x h(-1)) caused an up to fivefold increased in the alkaline secretion and the melatonin antagonist luzindole or cutting all peri-carotid nerves abolished the duodenal secretory response to i.c.v. phenylephrine. Peripheral melatonin thus stimulates duodenal mucosal HCO3- secretion and endogenous melatonin, very likely released from mucosal enterochromaffin cells, is involved in mediating neural stimulation of the secretion.
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PMID:Central nervous stimuli increase duodenal bicarbonate secretion by release of mucosal melatonin. 1178 66

Recently, a species-dependent distribution of melatonin binding sites have been found in lamina I-V and lamina X of the spinal cord. In order to learn more about the function of spinal melatonin receptors, we investigated (i) the gene expression for melatonin receptor subtypes in lumbar and thoracal spinal cord tissue by means of the reverse-transcriptase polymerase chain reaction (RT-PCR) technique, and (ii) the electrophysiological and pharmacological properties of melatonin receptors heterologously expressed in Xenopus oocytes after injection of spinal cord mRNA by means of the voltage clamp technique. Because ample evidence indicates an antinociceptive effect of melatonin, (iii) the role of spinal melatonin receptors for maintaining mechanical and thermal hyperalgesia was studied in a rat model for postoperative pain. The RT-PCR data revealed that transcripts for MT1 and MT2 melatonin receptors are present in the dorsal and ventral horn of lumbar and thoracal spinal cord tissue. Injection of mRNA from lumbar spinal cord tissue into Xenopus oocytes led to the functional reconstitution of melatonin receptors which activate calcium-dependent chloride inward currents. Melatonin responses were abolished by simultaneous administration of the antagonists, 2-phenylmelatonin and luzindole and were unaffected by the MT2 antagonist 4-phenyl-2-propionamidotetralin. Intrathecal administration of different melatonin doses (10-100 nmol) did not inhibit mechanical or thermal hyperalgesia. However, intrathecal application of a low dose of morphine together with melatonin caused a brief antinociceptive effect suggesting an enhanced morphine analgesia by melatonin. In conclusion, the present study demonstrated for the first time the presence of transcripts of MT1 and MT2 receptors located in the dorsal and ventral horn of the spinal cord. Furthermore, spinal melatonin enhanced the antinociceptive effect of morphine indicating that melatonin acts as a neuromodulator in the spinal cord.
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PMID:Gene expression and functional characterization of melatonin receptors in the spinal cord of the rat: implications for pain modulation. 1282 10

Systemically administered melatonin has been reported to produce antinociception and to inhibit spinal nociceptive transmission in rats. The present study was designed to investigate in anesthetized rats (i) whether intrathecally administered melatonin can depress synaptic potentiation (wind-up) in the spinal cord, and (ii) whether this effect is prevented by intrathecal (i.t.) administration of the MT2 receptor antagonist luzindole. Results showed that melatonin i.t. (10, 30 and 90 microg) induced dose-dependent inhibition of wind-up activity (ED50=52.06 microg i.t.), an effect that was prevented by 100 microg i.t. of luzindole. Since wind-up is dependent on NMDA receptor activation, the results suggest that melatonin can interfere with the NMDA-mediated glutamatergic component of pain transmission in rat spinal cord by acting on MT2 receptors.
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PMID:Melatonin-induced inhibition of spinal cord synaptic potentiation in rats is MT2 receptor-dependent. 1508 74

The present study assesses the antinociceptive effect of melatonin in chemical behavioral models of nociception and investigates some of the mechanisms underlying this effect. Melatonin administered by intraperitoneal (i.p., 10-100 mg/kg), intracerebroventricular (i.c.v., 250-500 pmol/site) and intraplantar (i.pl., 30-100 ng/i.pl.) routes, reduced in a dose-dependent manner the nociception caused by i.pl. injection of glutamate (10 micromol/paw), with mean ID50 values of 32.6 mg/kg, 200 pmol/site and 59 ng/i.pl., respectively. Furthermore, melatonin in the dose range of 10-100 mg/kg, i.p., reduced the neurogenic pain caused by i.pl. injection of capsaicin (5.2 nmol/paw) with inhibition of 48 +/- 4%. The antinociceptive effect of melatonin (100 mg/kg, i.p.) on glutamate-induced nociception was completely prevented by the pretreatment of animals with naloxone (a nonselective opioid receptor antagonist, 1 mg/kg, i.p.), ketanserin (a preferential 5-HT2A receptor antagonist, 1 mg/kg, i.p.), sulpiride (a D2 receptor antagonist, 50 mg/kg, i.p.), L-arginine (a precursor of nitric oxide, 600 mg/kg, i.p.), yohimbine (an alpha2-adrenoceptor antagonist, 0.15 mg/kg, i.p.) and luzindole (a preferential MT2 receptor antagonist, 10 mg/kg, i.p.), but was not affected by the pretreatment with D-arginine (an inactive isomer of L-arginine, 600 mg/kg, i.p.), prazosin (an alpha1-adrenoceptor antagonist, 0.15 mg/kg, i.p.) or after bilateral adrenalectomy. Collectively, present results suggest that melatonin produces peripheral and central antinociception when assessed on capsaicin- or glutamate-induced pain in mice through mechanisms that are likely mediated by interaction with plasma membrane-bound melatonin receptors and modulated by opioid, serotonergic (5-HT2A receptors), dopaminergic (D2-receptors), adrenergic (alpha2-adrenoceptors) systems as well as the L-arginine-nitric oxide pathway.
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PMID:Mechanisms involved in the antinociception caused by melatonin in mice. 1701 96

Melatonin is a hormone with endocrine, paracrine and autocrine actions. It is involved in the regulation of multiple functions, including the control of the gastrointestinal (GI) system under physiological and pathophysiological conditions. Since the gut contains at least 400 times more melatonin than the pineal gland, a review of the functional importance of melatonin in the gut seems useful, especially in the context of recent clinical trials. Melatonin exerts its physiological effects through specific membrane receptors, named melatonin-1 receptor (MT1), MT2 and MT3. These receptors can be found in the gut and their involvement in the regulation of GI motility, inflammation and pain has been reported in numerous basic and clinical studies. Stable levels of melatonin in the lower gut that are unchanged following a pinealectomy suggest local synthesis and, furthermore, implicate physiological importance of endogenous melatonin in the GI tract. Presently, only a small number of human studies report possible beneficial and also possible harmful effects of melatonin in case reports and clinical trials. These human studies include patients with lower GI diseases, especially patients with irritable bowel syndrome, inflammatory bowel disease and colorectal cancer. In this review, we summarize the presently available information on melatonin effects in the lower gut and discuss available in vitro and in vivo data. We furthermore aim to evaluate whether melatonin may be useful in future treatment of symptoms or diseases involving the lower gut.
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PMID:Distribution, function and physiological role of melatonin in the lower gut. 2202 77

Melatonin (MT) is a neurohormone synthesized and secreted by the pineal gland. MT plays an important role in the regulation of physiological and neuroendocrine functions. The purpose of this study was to assess the overall effect of melatonin on neuropathic pain, the type of melatonin receptor involved, and potential role of the opioid system and GABA(A) receptors. The experiments were conducted by using the animal neuropathic pain model (CCI). The rats with CCI showed the characteristic for the mechanical allodynia and thermal hyperalgesia signs that were calculated by using the von Frey's and Hargreaves' tests. The conducted studies measured the effects of intraperitoneal administration of naloxone (opioid antagonist), prazosin (MT3 antagonist), luzindole (MT1/MT2 receptor antagonist), picrotoxin (GABA(A) antagonist) and flumazenil (benzodiazepine antagonist) on the antinociceptive effects caused by melatonin. Melatonin caused the increase in the pain threshold of the mechanical allodynia and the slight increase in the threshold of the thermal hyperalgesia. The pre-treatment with naloxone completely abolished the antinociceptive effects of melatonin in von Frey's test, but not thermal sensation in the Hargreaves's test. Prazosin did not have any effects, while administration of luzindole significantly suppressed the antinociceptive effect of melatonin. The antiallodynic effect of MT was also abolished by flumazenil and picrotoxin. Melatonin influences the mechanical allodynia but not thermal hyperalgesia via activation of opioid system and benzodiazepine-GABAergic pathway. Antinociceptive effects of melatonin are mostly related to the MT1/MT2 receptors interaction.
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PMID:Exogenous melatonin abolishes mechanical allodynia but not thermal hyperalgesia in neuropathic pain. The role of the opioid system and benzodiazepine-gabaergic mechanism. 2338 80

Melatonin, the hormone of darkness has many physiological functions in the body and also exerts a number of pharmacological effects. Most of these actions of melatonin are mediated through melatonin membrane receptors like MT1/MT2 receptors or through nuclear orphan receptors like RZR/ROR receptors or through calcium binding proteins in the cytosol. The finding that pain perception is circadian in nature has prompted many to suggest that "pain modulation" is one of the most important physiological functions of melatonin. By using a number of animal models of pain perception, it has been found that melatonin exerts antinociceptive and antiallodynic effects. Number of studies has shown that melatonin modulates pain perception by acting through opioid receptors, NMDA receptors and G-protein, and they have been analyzed using specific antagonists like naloxone or NMDA-G protein receptor antagonists. Recently it has been shown that melatonin exerts its antinociceptive effects through MT1 and MT2 melatonergic receptors located in the dorsal region of the spinal cord as well as in various parts of the brain concerned with pain modulation. Evidences for this have been obtained by using common melatonergic receptor antagonist like luzindole or specific MT2 receptor antagonist like 4P-PDOT or K-185. In a few clinical studies undertaken during surgery, melatonin has been shown to have analgesic effects. Melatonin is emerging as a new analgesic drug with a novel mechanism of actions and has the potential to be used as a natural pain killer in inflammatory, neuropathic pain conditions and also during surgical procedures.
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PMID:Melatonin and its agonists in pain modulation and its clinical application. 2347 60

Neuropathic pain is an important public health problem for which only a few treatments are available. Preclinical studies show that melatonin (MLT), a neurohormone acting on MT1 and MT2 receptors, has analgesic properties, likely through MT2 receptors. Here, we determined the effects of the novel selective MLT MT2 receptor partial agonist N-{2-([3-bromophenyl]-4-fluorophenylamino)ethyl}acetamide (UCM924) in 2 neuropathic pain models in rats and examined its supraspinal mechanism of action. In rat L5-L6 spinal nerve ligation and spared nerve injury models, UCM924 (20-40 mg/kg, subcutaneously) produced a prolonged antinociceptive effect that is : (1) dose-dependent and blocked by the selective MT2 receptor antagonist 4-phenyl-2-propionamidotetralin, (2) superior to a high dose of MLT (150 mg/kg) and comparable with gabapentin (100 mg/kg), but (3) without noticeable motor coordination impairments in the rotarod test. Using double staining immunohistochemistry, we found that MT2 receptors are expressed by glutamatergic neurons in the rostral ventrolateral periaqueductal gray. Using in vivo electrophysiology combined with tail flick, we observed that microinjection of UCM924 into the ventrolateral periaqueductal gray decreased tail flick responses, depressed the firing activity of ON cells, and activated the firing of OFF cells; all effects were MT2 receptor-dependent. Altogether, these data demonstrate that selective MT2 receptor partial agonists have analgesic properties through modulation of brainstem descending antinociceptive pathways, and MT2 receptors may represent a novel target in the treatment of neuropathic pain.
Pain 2015 Feb
PMID:Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways. 2559 52

Melatonin is a neurohormone involved in the regulation of both acute and chronic pain whose mechanism is still not completely understood. We have recently demonstrated that selective MT2 melatonin receptor partial agonists have antiallodynic properties in animal models of chronic neuropathic pain by modulating ON/OFF cells of the descending antinociceptive system. Here, we examined the antinociceptive properties of the selective MT2 melatonin receptor partial agonists N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide (UCM765) and N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide (UCM924) in two animal models of acute and inflammatory pain: the hot-plate and formalin tests. UCM765 and UCM924 (5-40 mg/kg, s.c.) dose-dependently increased the temperature of the first hind paw lick in the hot-plate test, and decreased the total time spent licking the injected hind paw in the formalin test. Antinociceptive effects of UCM765 and UCM924 were maximal at the dose of 20mg/kg. At this dose, the effects of UCM765 and UCM924 were similar to those produced by 200 mg/kg acetaminophen in the hot-plate test, and by 3 mg/kg ketorolac or 150 mg/kg MLT in the formalin test. Notably, antinociceptive effects of the two MT2 partial agonists were blocked by the pre-treatment with the MT2 antagonist 4-phenyl-2-propionamidotetralin (4P-PDOT, 10 mg/kg) in both paradigms. These results demonstrate the antinociceptive properties of UCM765 and UCM924 in acute and inflammatory pain models and corroborate the concept that MT2 melatonin receptor may be a novel target for analgesic drug development.
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PMID:Antinociceptive properties of selective MT(2) melatonin receptor partial agonists. 2616 99

Melatonin (MLT; N-acetyl-5-methoxytryptamine) exhibits analgesic properties in chronic pain conditions. While researches linking MLT to epigenetic mechanisms have grown exponentially over recent years, very few studies have investigated the contribution of MLT-associated epigenetic modification to pain states. Here, we report that together with behavioral allodynia, spinal nerve ligation (SNL) induced a decrease in the expression of catalytic subunit of phosphatase 2A (PP2Ac) and enhanced histone deacetylase 4 (HDAC4) phosphorylation and cytoplasmic accumulation, which epigenetically alleviated HDAC4-suppressed hmgb1 gene transcription, resulting in increased high-mobility group protein B1 (HMGB1) expression selectively in the ipsilateral dorsal horn of rats. Focal knock-down of spinal PP2Ac expression also resulted in behavioral allodynia in association with similar protein expression as observed with SNL. Notably, intrathecal administration with MLT increased PP2Ac expression, HDAC4 dephosphorylation and nuclear accumulation, restored HDAC4-mediated hmgb1 suppression and relieved SNL-sensitized behavioral pain; these effects were all inhibited by spinal injection of 4P-PDOT (a MT2 receptor antagonist, 30 minutes before MLT) and okadaic acid (OA, a PP2A inhibitor, 3 hr after MLT). Our findings demonstrate a novel mechanism by which MLT ameliorates neuropathic allodynia via epigenetic modification. This MLT-exhibited anti-allodynia is mediated by MT2-enhanced PP2Ac expression that couples PP2Ac with HDAC4 to induce HDAC4 dephosphorylation and nuclear import, herein increases HDAC4 binding to the promoter of hmgb1 gene and upregulates HMGB1 expression in dorsal horn neurons.
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PMID:Melatonin relieves neuropathic allodynia through spinal MT2-enhanced PP2Ac and downstream HDAC4 shuttling-dependent epigenetic modification of hmgb1 transcription. 2673 38


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