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)

Extensive studies in rodents suggest that serotonin (5-HT) modulates nociceptive responses through the stimulation of several receptor types. However, it remains to demonstrate that these receptors participate in the control of nociception under physiological conditions. Pain behaviors of mutants which do not express 5-HT1A, 5-HT1B, 5-HT2A or 5-HT3A receptors, or lacking the 5-HT transporter, compared to paired wild-type mice of the same genetic background, were examined using validated tests based on different sensory modalities. Mechanical (von Frey filaments, tail pressure, tail clip tests), thermal (radiant heat, 46 degrees C water bath, hot-plate test) and formalin-induced nociception were determined in 2- to 3-month-old males. 5-HT1A knock-out mice differed from wild-types by higher thermal sensitivity (hot-plate test only), and 5-HT1B knock-out mice by higher thermal and formalin sensitivity. Both 5-HT2A and 5-HT3A knock-out mice differed from wild-types by a dramatic decrease in the formalin-induced nociceptive responses for phase II (16-45 min after injection/inflammatory phase). In contrast, neither mechanical, thermal nor formalin-induced nociception differed between mutants lacking the 5-HT transporter and paired wild-type mice. Although differences in spontaneous locomotor activity in 5-HT1B-/- (increase) and 5-HT3A-/- (decrease) knock-out mice versus paired wild-types might have confounded differences in nociception, acute 5-HT receptor blockade by selective antagonists was found to replicate in wild-type mice the effects on pain behavior, but not on locomotor activity, of the respective gene knock-out in mutants. These results support the conclusion that the complex control of pain mechanisms by 5-HT, acting at multiple receptors, is physiologically relevant in mice.
Pain 2007 Aug
PMID:Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice. 1725 Sep 64

Several lines of evidence suggest that descending serotoninergic facilitatory pathways are involved in neuropathic pain. These pathways may involve 5-HT2A receptors known to play a role in spinal and peripheral sensitization. The implication of this receptor in neuropathy was investigated in a model of peripheral neuropathy induced by 2',3'-dideoxycytidine, a nucleoside analogue with reverse transcriptase inhibitory properties used in HIV/AIDS therapy. Four days after a single 100mg/kg i.v. administration in the tail vein, mitochondrial alterations in nociceptive and non-nociceptive dorsal root ganglion cells were observed at the lumbar level. These alterations were not associated with TUNEL labelling or with modification of the total number of dorsal root ganglion cells. At the same time point, 5-HT2A receptor immunolabelling was increased throughout the dorsal horn (by 49.5% in layer II and 57.8% in layer III). The number of 5-HT2A receptor immunoreactive neurons in the dorsal root ganglion was also increased by 30.7%. Four days after 2',3'-dideoxycytidine administration, rats had developed thermal allodynia as well as mechanical hyperalgesia and allodynia, which dose-dependently decreased after epidural injection of MDL 11,939, a 5-HT2A receptor antagonist. Moreover, 5-HT2A receptor knock-out mice did not develop 2',3'-dideoxycytidine-induced neuropathy whereas their control littermates displayed a neuropathy comparable to that observed in rats. Our data show that 2',3'-dideoxycytidine-induced neuropathy is associated with alterations of nociceptive and non-nociceptive peripheral cells and that the 5-HT2A receptor is involved in the peripheral sensitization of nociceptors as well as in a wide central sensitization of dorsal horn neurons.
Pain 2008 Jul
PMID:Role of spinal serotonin 5-HT2A receptor in 2',3'-dideoxycytidine-induced neuropathic pain in the rat and the mouse. 1788 73

The analgesic effects of tramadol are considered to be mediated by both the opioid system and the serotonergic system. This study investigated the involvement of a subtype of serotonin receptors, 5-hydroxytryptamine (5-HT)2A receptor, in the analgesic effect of tramadol. The intraperitoneal (i.p.) injection of tramadol reduced the paw withdrawal latency (PWL) to radiant heat testing in mono-arthritic rats. The antagonistic effect of i.p. ketanserin (a 5-HT2A receptor antagonist) on tramadol analgesia was observed. The expression of the 5-HT2A receptor mRNA in the nucleus of raphe magnus (NRM), ventrolateral periaqueductal gray (vlPAG) and spinal dorsal horn of mono-arthritic rats after a ten-day treatment with tramadol was measured with in situ hybridization. Either single injections or 10 days of tramadol treatment dose-dependently elevated PWL of arthritic rats while ketanserin could partially antagonize the tramadol analgesic effect. Expression of the 5-HT2A receptor mRNA in NRM, ipsilateral vlPAG, and the ipsilateral spinal dorsal horn of arthritic rats was significantly increased after tramadol treatment. These results suggest that 5-HT2A receptors are involved in the analgesic effect of tramadol. This study provides evidence for involvement of 5-HT2A receptors in the tramadol analgesia of inflammatory pain. The increase in this receptor mRNA in the chronic study may contribute to the sustaining effect of tramadol long-term treatments in clinical practice.
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PMID:Involvement of serotonin 2A receptors in the analgesic effect of tramadol in mono-arthritic rats. 1841 4

The present study examined the contribution of 5-hydroxytryptamine (5-HT) to acute peripheral inflammatory pain in rats. We used formalin test in this study. After formalin injection into the rat hind paw, biphasic pain-related behavior (phases 1 and 2) was observed. A microdialysis study revealed that 5-HT was released into the formalin injection site in a formalin concentration-dependent manner (1.25-5%), and its peak time was 18min after the injection. Previous studies suggest that peripheral 5-HT2 receptors are involved in inflammatory pain. Therefore, we next examined whether 5-HT2A and 5-HT2C receptors are involved, and from where 5-HT is released in the formalin test. Local pretreatment with a selective 5-HT2A receptor antagonist, ketanserin, and selective 5-HT2C receptor antagonists, RS102221 and SB242084, inhibited the number of flinches in early part of phase 2 (phase 2A) of the formalin test in a dose-dependent manner. Peripheral pretreatment with sodium cromoglycate (cromolyn), a mast cell membrane stabilizer, completely suppressed 5-HT release and inhibited phase 2 responses of the formalin test. These drugs inhibited c-fos expression in the superficial layer of the spinal dorsal horn of segments L4-5 at 2h after formalin injection. These results indicate that 5-HT released into peripheral tissue and its receptors, 5-HT2A as well as 5-HT2C, at the periphery have an important role in pain-related behaviors during acute peripheral inflammation.
Eur J Pain 2009 May
PMID:The nociceptive mechanism of 5-hydroxytryptamine released into the peripheral tissue in acute inflammatory pain in rats. 1865

We recently showed that peripheral and spinal 5-HT2A receptors (5-HT2AR) are involved in a rodent model of neuropathy induced by a nucleoside analogue reverse transcriptase inhibitor. In this paper, we show that 5-HT2AR are also involved in neuropathy induced by an anti-neoplasic drug, vincristine. Vincristine-treated rats (0.1mg/kg, daily i.p. administration for two 5-day cycles) developed thermal allodynia and mechanical hypersensitivity, which decreased in a dose-related manner after epidural injection a 5-HT2A receptor antagonist. Moreover, 5-HT2A-/- mice did not develop vincristine-induced neuropathy contrarily to their 5-HT2A+/+ littermates. In vincristine-treated rats, the number of nociceptive dorsal root ganglion cells expressing the 5-HT2AR was increased by 38%, and 5-HT2AR immunolabelling was enhanced in layers I-IV of the dorsal horn. At the EM level, a 76.3% increase in the density of 5-HT2AR immunopositive axon terminals within superficial layers of the dorsal horn was noted after vincristine treatment. Immunocytochemical study of Fos expression in vincristine-treated rats revealed a significant increase in the number of Fos-positive neurons not only in regions where nociceptive fibres terminate superficial (I-II) and deep layers (V-VI) of the spinal cord, but also in intermediate layers, suggesting that Abeta fibres could be involved in the spinal sensitization observed in this model. Double labelling experiments showed that Fos-positive neurons were endowed with 5-HT2AR immunolabelling in the dorsal horn of vincristine-treated rats. These data provide support to the idea that, in vincristine-induced neuropathy, 5-HT2AR are involved in the sensitization of peripheral nociceptors and spinal nociceptive processing.
Pain 2008 Nov 30
PMID:Serotonin 5-HT2A receptor involvement and Fos expression at the spinal level in vincristine-induced neuropathy in the rat. 1893 May 97

This study assesses the antinociceptive effect induced by different dosages of topiramate (TP), an anticonvulsant drug that is orally administered in models of neuropathic pain and acute pain in rats and mice, respectively. Orally administered TP (80 mg/Kg) in mice causes antinociception in the first and second phases of a formalin test, while in doses of 20 and 40 mg/Kg it was only effective in the second phase. TP (80 mg/Kg, p.o) also exhibited antinociceptive action in the hot plate test, however, it did not have an effect in the capsaicin test in mice, nor in the model of neuropathic pain in diabetic rats. The antinociceptive effect caused by TP (80 mg/Kg, p.o) in the formalin test was reversed by prior treatment with naloxone (opioid antagonist), but not with glibenclamide (antagonist of the potassium channel), ondansetron (antagonist of the serotonin 5HT3 receptor) or cyproheptadine (antagonist of the serotonin 5HT2A receptor).The data show that TP has an important antinociceptive effect in the models of nociception induced by chemical (formalin) or thermal (hot plate) stimuli, and that the opioid system plays a part in the antinociceptive effect, as shown by formalin.
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PMID:Antinociceptive effect of topiramate in models of acute pain and diabetic neuropathy in rodents. 1905 4

Several lines of evidence indicate that peripheral 5-HT2A receptors are involved in the development of inflammatory and neuropathic pain. However, their localization in sensory cell bodies is not accurately known. We therefore studied 5-HT2A receptor distribution in rat lumbar dorsal root ganglia using immunocytochemistry. Forty percent of L3 lumbar dorsal root ganglion cells were immunoreactive for 5-HT2A receptor. Most were small- to medium-sized cell bodies. Double-labeled experiments revealed that they expressed various chemical phenotypes. The smaller 5-HT2AR cell bodies often bind the isolectin B4 although some 5-HT2AR cell bodies also express substance P (SP). Many 5-HT2A-positive small dorsal root ganglion cells expressed the capsaicin receptor transient receptor potential vanilloid type 1 receptor (TRPV1), confirming their nociceptive nature. In addition, a few large cell bodies were labeled for 5-HT2A, and they also expressed NF200 suggesting that they were at the origin of Adelta or Abeta fibers. A total absence of double labeling with parvalbumin showed that they were not proprioceptors. 5-HT2A immunoreactivity in dorsal root ganglia cells was found in the cytoplasm and along the plasma membrane at the interface between sensory cell and the adjacent satellite cells; this distribution was confirmed under the electron microscope, and suggested a functional role for the 5-HT2A receptor at these sites. We therefore investigated the presence of 5-HT and 5-HIAA in lumbar dorsal root ganglia by high performance liquid chromatography. There were 5.75+/-0.80 ng 5-HT and 3.19+/-0.37 ng 5-hydroxyindoleacetic acid (5-HIAA) per mg of protein with a ratio 5-HIAA/5-HT of 0.67+/-0.10, similar to values typically observed in brain tissues. These findings suggest that 5-HT, via the 5-HT2AR, may be involved in the peripheral control of sensory afferents, mainly unmyelinated nociceptors and to a lesser extent neurons with Adelta or Abeta fibers, and in the control of cellular excitability of some dorsal root cell bodies through a paracrine mechanism of action.
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PMID:The 5-HT2A receptor is mainly expressed in nociceptive sensory neurons in rat lumbar dorsal root ganglia. 1936 28

There are gene polymorphisms changing the expression or activation of the serotonin (5-HT) receptors, which are associated with pain. This review showed an availability of 5-HT2A receptor gene polymorphism in analgesic sensitivity. To search gene polymorphisms related to analgesic sensitivity is important to further effective pain management. In future 5-HT2A receptor gene polymorphisms, together with polymorphisms of other genes, may greatly contribute to effective postoperative pain management and personalized medicine.
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PMID:[Serotonin receptor gene polymorphism and analgesic sensitivity]. 1976 36

Serotonin is involved in several central nervous system functions including pain threshold, mood regulation and drug reward. Overuse of acute medications is commonly identified as a causative factor for medication overuse headache (MOH). Apparently, MOH shares with other kinds of drug addiction some common neurobiological pathways. The objective of this study is to assess the role of serotonin metabolism genes in the genetic liability to MOH. We performed a genetic association study using polymorphisms of five serotonin metabolism-related genes: serotonin transporter (5HTT), serotonin receptor 1A(5-HT1A), serotonin receptor 1B (5-HT1B), serotonin receptor 2A (5-HT2A) and serotonin receptor 6 (5HT6)genes. We compared 138 patients with MOH with a control sample of 117 individuals without headache and without drug overuse, and with 101 patients with migraine without aura but without drug overuse (MO). The genotypic and allelic distributions of all polymorphisms investigated didnot differ among the three groups. In conclusion, our studydoes not provide evidence that the 5HTT, 5-HT1A, 5HT1B,5HT2A and 5HT6 gene polymorphisms play a role in the genetic predisposition to MOH.
J Headache Pain 2010 Feb
PMID:Lack of association between five serotonin metabolism-related genes and medication overuse headache. 1993 17

Neurotransmitter serotonin (5-HT) released from descending pain modulation pathways to the dorsal horn is crucial to spinal nociception processing. This study sought to gain insight into the modulatory roles of specific serotonin receptor subtypes in experimentally induced neuropathic pain. In rats subjected to spinal nerve ligation (SNL) surgery, we recorded field potentials evoked in the spinal dorsal horn by C fibre-input, during spinal superfusion with subtype-selective drugs. In neuropathic rats, subtype 5-HT1A agonist 8-OH-DPAT (100 nM) was found to potently depress evoked field potentials, as opposed to 5-HT2A or 5-HT2B subtype agonists TCB-2 (100 nM) or BW 723C86 (1 microM), respectively, which consistently enhanced evoked potentials. All three failed to alter spinal field potentials in sham operated rats. CP 94253 (1 microM), WAY 161503 (1 mM) or SR 57227 (at 1 microM in SNL rats, and 100 microM in sham rats), selective agonists for 5-HT1B, 5-HT2C and 5-HT3 receptors, respectively, significantly depressed evoked field potentials in both animal groups. The 5-HT4 agonist RS 67333 (1 microM) was depressant only in sham operated animals. Only after SNL, spinal superfusion with 5-HT1A- or 5-HT1B receptor-antagonists (S)-WAY 100135 (100 microM) or SB 224289 (100 microM), respectively, disinhibited C fibre-evoked potentials, whereas 5-HT2A or 5-HT2B receptor-antagonists 4F 4PP (100 microM) or SB 204741 (100 microM) depressed evoked potentials, suggesting tonic activity of all four subtypes as a consequence of experimental nerve injury. The present findings reveal profound subtype-specific changes in the functional modulatory activities of spinal serotonin receptors following peripheral nerve injury. In particular, spinal hyperexcitation promoted by receptors 5-HT2A and 5-HT2B is suggested as a novel pathogenic pathway contributing to neuropathic pain.
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PMID:Subtype-specific changes in 5-HT receptor-mediated modulation of C fibre-evoked spinal field potentials are triggered by peripheral nerve injury. 2041 34


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