Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the last few years, there has been a great increase in our understanding of pain mechanisms. Given the complexity of the mechanisms involved in pain modulation, it is surprising that the pharmacological control of pain through the application of relatively simple analgesics can be effective. Nevertheless, the application of single analgesics is not always effective in diverse painful conditions such as chronic pain syndromes. In these circumstances, we can take advantage of the complexity of pain regulation and try to identify new targets in these intricate processes. It is becoming clear that the combination of different mechanisms, which improves efficacy with reduced toxicity, is necessary for the reliable pharmacotherapy of pain, and is at the forefront in the search for better analgesics. Serotonin is involved at multiple levels in the regulation of nociception. In particular, the raphe nuclei may play a crucial role in integrating the nociceptive and affective information through descending projections to the spinal cord and ascending projections to the forebrain. In these nuclei, 5-HT1A receptors function as somatodendritic autoreceptors controlling the release of serotonin in terminal areas. Different studies have shown that, by preventing this inhibitory control of serotonin release, it is possible to enhance the analgesic effect of drugs that increase serotonin levels (i.e. antidepressants, opiates, and non-steroidal anti-inflammatory drugs) by facilitating descending, and also ascending, pathways involved in pain modulation. Therefore, 5-HT1A receptors may be used as a new target in the search for new pharmacological approaches in the augmentation of analgesia.
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PMID:The role of 5-HT1A receptors in research strategy for extensive pain treatment. 1701 70

We used a model of neuropathic pain consisting of rats with chronic constriction injury (CCI) of the sciatic nerve, in order to investigate whether endocannabinoid levels are altered in the dorsal raphe (DR) and to assess the effect of repeated treatment with (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate, a synthetic cannabinoid agonist, or N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404), an inhibitor of endocannabinoid reuptake, on DR serotonergic neuronal activity and on behavioural hyperalgesia. CCI resulted in significantly elevated anandamide but not 2-arachidonoylglycerol levels in the DR. Furthermore, as well as thermal and mechanical hyperalgesia, CCI caused serotonergic hyperactivity (as shown by the increase of basal activity of serotonergic neurones, extracellular serotonin levels and expression of 5-HT1A receptor gene). Repeated treatment with either (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate or AM404 reverted the hyperalgesia and enhanced serotonergic activity induced by CCI in a way attenuated by N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide, a selective cannabinoid subtype 1 (CB1) receptor antagonist. Despite the elevated levels of anandamide following CCI, N-piperidino-5-(4-chlorophenyl)-1-(2,4dichlorophenyl)-4-methyl-3-pyrazolecarboxamide did not produce hyperalgesia or any other effect on serotonergic neuronal activity when administered alone. Furthermore, the effects of AM404 were not accompanied by an increase in endocannabinoid levels in the DR. In conclusion, following CCI of the sciatic nerve, the endocannabinoid and serotonergic systems are activated in the DR, where repeated stimulation of CB1 receptors with exogenous compounds restores DR serotonergic activity, as well as thermal and mechanical nociceptive thresholds, to pre-surgery levels. However, an elevated level of endogenous anandamide in the DR does not necessarily contribute to the CB1-mediated tonic control of analgesia and serotonergic neuronal activity.
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PMID:Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system. 1704 Apr 73

The mechanism of action of acetaminophen is currently widely discussed. Direct inhibition of cyclooxygenase isoforms remains the commonly advanced hypothesis. We combined behavioral studies with molecular techniques to investigate the mechanism of action of acetaminophen in a model of tonic pain in rats. We show that acetaminophen indirectly stimulates spinal 5-hydroxytryptamine (5-HT)1A receptors in the formalin test, thereby increasing transcript and protein levels of low-affinity neurotrophin receptor, insulin-like growth factor-1 (IGF-1) receptor alpha subunit, and growth hormone receptor and reducing the amount of somatostatin 3 receptor (sst3R) mRNA. Those cellular events seem to be important for the antinociceptive activity of acetaminophen. Indeed, down-regulation of sst3R mRNA depends on acetaminophen-elicited, 5-HT1A receptor-dependent increase in neuronal extracellular signal-regulated kinase 1/2 (ERK1/2) activities that mediate antinociception. In addition, spinal growth hormone (GH) and IGF-1 receptors would also be involved in the antinociceptive activity of the analgesic at different degrees. Our results show the involvement of specific 5-HT1A receptor-dependent cellular events in acetaminophen-produced antinociception and consequently indicate that inhibition of cyclooxygenase activities is not the exclusive mechanism involved. Furthermore, we propose that the mechanisms of 5-HT1A receptor-elicited antinociception and the role of the spinal ERK1/2 pathway in nociception are more intricate than suspected so far and that the GH/IGF-1 axis is an interesting new player in the regulation of spinal nociception.
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PMID:Acetaminophen recruits spinal p42/p44 MAPKs and GH/IGF-1 receptors to produce analgesia via the serotonergic system. 1708 3

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

The present study was undertaken to evaluate the potential role of 5-HT1A receptors in the antidepressant-like effect and antinociceptive effect of venlafaxine. With this aim, the effect of either a selective 5-HT1A receptor antagonist (WAY-100635; N-2-[4-(2-methoxyphenyl-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexane carboxamide) or a selective 5-HT1A receptor agonist (8-OH-DPAT; 8-hydroxy-2-(di-n-propylamine) tetralin hydrobromide) was investigated in mice in combination with venlafaxine by means of the forced swimming test, a paradigm aimed at screening potential antidepressants, and the hot-plate test, a phasic pain model. Surprisingly, the results showed that WAY-100635 produced a large decrease in the antidepressant-like effect of venlafaxine, while 8-OH-DPAT rendered effective a non-effective dose of this antidepressant. However, in the hot-plate test WAY-100635 significantly enhanced the antinociceptive effect of venlafaxine, whereas 8-OH-DPAT counteracted its antinociceptive effect. These findings show that 5-HT1A receptors play differing roles in modulating the antidepressant-like and antinociceptive effects of venlafaxine in the models investigated. The results imply that blockade of the 5-HT1A receptors in the forebrain will counteract the favourable (antidepressant-like) effect at raphe nuclei level, and consequently, the overall effect evidenced is an antagonism. This suggests a predominant role of 5-HT1A receptors located in the forebrain area for the antidepressant-like effect. In contrast, the antinociceptive effect of venlafaxine is probably potentiated due to the blockade of somatodendritic 5-HT1A receptors in the same raphe nuclei, facilitating the descending monoaminergic pain control system.
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PMID:Role of serotonin 5-HT1A receptors in the antidepressant-like effect and the antinociceptive effect of venlafaxine in mice. 1840 17

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

Adjuvant drugs that can delay tolerance to morphine analgesia may lead to improved management of pain in chronic disease such as cancer. This study was aimed to investigate effect of buspirone, as a partial agonist of 5-HT1A receptor, on tolerance induced to morphine analgesic effect in animals with skin cancer. Study was carried on female Swiss albino mice. For skin tumorigensis, mice were treated with single dose of 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by multiple dose of croton oil. Tolerance to morphine analgesia was induced by daily subcutaneous (sc) injection of morphine (5mg/kg for 30 days) and assayed by using the hot plate method. Results obtained from this study showed that pain threshold in mice with skin cancer were significantly lower. Tolerance to analgesic effect of morphine (5 mg/kg, sc) was appeared at day 15, whereas, in normal and skin tumor bearing mice co-treated daily with morphine (5 mg/kg, sc) and three different intraperitoneal (ip) doses of buspirone (5, 7.5 and 10 mg/kg) tolerance was observed at days 25 and 30. In conclusion our data indicate that concurrent use of morphine with buspirone may produce good cancer pain control and attenuate development of tolerance.
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PMID:Buspirone attenuates tolerance to analgesic effect of morphine in mice with skin cancer. 2036

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

New data on complex realization of anxiolytic, antidepressive and antinociceptive effects of prenatal injections of a 5-HT1A agonist buspirone were obtained in prenatally stressed adult rats. Buspirone was injected to female rats from the 9th to 21st days of pregnancy; during the last week of pregnancy buspirone was injected 10 min before immobilization stress. In the adult offspring of both sexes, behavioral indices of tonic pain response in the formalin test and the indices of depression in the forced swim test were investigated. The choice of the target was defined in accordance with available literature data on the role of 5-HT1A receptors in the mechanisms of prenatal stress, of formation of the ascending link of the nociceptive system, of development of depression, and in the mechanisms of the treatment ofnociceptive information. Prenatal stress increased the duration of licking and the time of immobility, the indices of tonic pain and depression in the rats of both sexes. Buspirone evoked the decrease of the indices investigated in prenatally stressed rats in both tests in comparison with the relevant indices in prenatally stressed rats that were not subjected to buspirone. Thereby, it has been demonstrated that buspirone normalized the indices of the tonic pain response modified by prenatal stress; a considerable decrease of the index of depression suggests that there are differences in mechanisms of antinociceptive and antidepressive effects of buspirone. The data on complex realization of anxiolytic, antidepressive and antinociceptive effects ofbuspirone stimulate the attention of clinicians and prompt further investigations in this direction.
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PMID:[Effects of prenatal influences of buspirone and stress on indices of inflammatory pain response and depressive behaviour in adult rats]. 2056 60

Previous investigations from our laboratory demonstrated that prenatal stress exacerbates inflammatory pain-related behavior in adult rats and that fetal serotonin (5-HT) is involved in this phenomenon. In the present study we test the hypothesis that injections of buspirone, a 5-HT1A agonist, to rat dams before restraint stress during the last week of pregnancy (between pregnant days 15 and 20) can improve the characteristics of emotional and inflammatory pain-related behaviors in the adult offspring. Buspirone was injected to dams between the 9 and 20 days of pregnancy, during restraint stress, five min before it. The depression-like behavior in the forced swim test, formalininduced pain and body weight were investigated in the adult offspring. Prenatal stress exacerbated the licking behavior, the index of formalin-induced pain, and increased the time of immobility, the index of depression-like behavior. Buspirone normalized the licking behavior and profoundly reduced the time of immobility, which indicates differences in the mechanisms of antinociceptive and antidepressant effects of buspirone. The present new findings demonstrate that adverse influences of prenatal stress on emotional and inflammatory pain-related behaviors can be prevented by using prenatal buspirone, which shows long-term anxiolytic, antidepressant and antinociceptive effects. The new fact of body weight decrease in buspirone+stress males is worth noting in the context of the important problem of body weight gain as a common side effect of treatment with antidepressant drugs.
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PMID:Maternal buspirone protects against the adverse effects of in utero stress on emotional and pain-related behaviors in offspring. 2105 51


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