Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08908 (5-HT1A)
 5,574 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

Japanese quail, selectively bred for long (LTI) and short (STI) tonic immobility (TI) responses, are thought to represent high and low fear groups, respectively. To study the neurochemical mechanisms underlying the behavioral distinctions, binding parameters were determined at the benzodiazepine, 5-HT1A, 5-HT3, alpha 2, and opioid receptor sites in the forebrains of the two lines. No differences were found in 5-HT1A, 5-HT3, alpha 2, mu- or kappa-opioid receptor binding between the lines. The KD for the binding of [3H]-flunitrazepam at the benzodiazepine receptor was significantly greater in the LTI than in the STI birds, indicating lower affinity for benzodiazepine ligands. The lines did not differ in benzodiazepine receptor number. Using [3H]-naltrindole, the LTI line was found to have fewer delta-opioid receptors than the STI line; the birds did not vary with respect to the affinity of these receptors. Thus, the selective breeding of the two lines has resulted in differences in benzodiazepine and delta-opioid binding, and these could produce differences in activity levels, fear, and pain responses, all of which could contribute to the tonic immobility response.
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PMID:Receptor binding in Japanese quail selected for long or short tonic immobility. 786 16

In this study, we examined whether activation of 5-HT1A receptors elicits antinociception in response to acute noxious chemical, thermal and mechanical stimuli in mice. In the writhing test, both agonists (e.g., 8-OH-DPAT, S 14671 and WY 50,324) and partial agonists (e.g., buspirone and gepirone) elicited a pronounced antinociception. However, antagonists (e.g., (-)-alprenolol and WAY 100,135) also induced antinociception and, at lower (inactive) doses, failed to modify the action of agonists. In addition, the separation between doses required for induction of antinociception as compared to those required for induction of ataxia (in the rotarod test) was variable and low for both agonists (median: 1.9) and partial agonists (median: 1.3), although it was somewhat greater for antagonists (> or = 3.3). In the hot-plate test, only certain agonists (e.g., 8-OH-DPAT) and partial agonists (e.g., gepirone) elicited antinociception and their actions were not attenuated by 5-HT1A antagonists which, themselves, were inactive in this paradigm. The 5-HT1C/2 antagonist, ritanserin, the 5-HT3 antagonist, ondansetron, the dopamine D2 receptor antagonist, raclopride, and the alpha 1-adrenoceptor antagonist, prazosin, were also ineffective in modifying the antinociception evoked by 5-HT1A agonists and partial agonists in the hot-plate test. In contrast, their actions were strongly attenuated by the alpha 2-adrenoceptor antagonist, idazoxan. In the tail-flick tests to noxious heat and noxious pressure, 5-HT1A receptor agonists, partial agonists and antagonists generally failed to induce antinociception. Moreover, modulation of stimulus intensity (from very weak to very intense) did not reveal any influence upon the latency to respond. In conclusion, in the writhing test, the data provide no evidence for a specific antinociceptive effect of the activation of 5-HT1A receptors. Further, in the hot-plate test, for those 5-HT1A agonists and partial agonists which induce antinociception, alpha 2-adrenoceptors rather than 5-HT1A receptors are implicated in their actions. Finally, in reflexive tests, irrespective of stimulus quality or intensity, 5-HT1A agonists and partial agonists do not mediate antinociception. These data suggest that the activation of 5-HT1A receptors does not, under these conditions of acute noxious stimulation, elicit antinociception.
Pain 1994 Jul
PMID:Serotonin and pain: evidence that activation of 5-HT1A receptors does not elicit antinociception against noxious thermal, mechanical and chemical stimuli in mice. 797 Aug 39

Parasites have been shown to have a broad range of effects on host behavior, including alterations of host responses to predators. Response to the threat of predation consist of a number of defensive behaviors, including a reduction in pain sensitivity and the induction of analgesia. The present study examined the relationships between subclinical (i.e., nonpathological) infection with the naturally occurring, enteric, sporozoan (coccidian) parasite, Eimeria vermiformis, predator exposure, and nociceptive responses in male mice. Brief (30 s) exposure of nonparasitized mice to a predator (a cat) induced marked, relatively short-lived analgesia that was insensitive to naloxone and blocked by the serotonin-1A (5-HT1A) agonist, 8-OH-DPAT. In contrast, mice acutely infected for 6 days with E. vermiformis, failed to show a predator-induced analgesia. The parasitized mice did display a naloxone-sensitive hypoalgesia or analgesia. However, restraint-stressed mice, which displayed a naloxone-sensitive hypoalgesia similar in amplitude to that of the infected mice, still exhibited a nonopioid mediated, predator-induced analgesia. These observations indicate that parasite infection attenuates 5-HT1A-sensitive predator-induced analgesia and likely reduces the accompanying fear and anxiety related anticipatory defense reactions of the host to the predator.
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PMID:Parasite infection attenuates nonopioid mediated predator-induced analgesia in mice. 819 Jul 69

The midbrain periaqueductal gray (PAG) is involved in a variety of functions including pain modulation, vocalization, autonomic control, fear and anxiety. This area contains serotonin receptors, particularly 5-HT1A that are known to play a role in the above functions. The goals of this study were to characterize the effects of 8-OH-DPAT, a selective 5-HT1A agonist, on the firing characteristics and membrane properties of PAG neurons. Both in vivo and in vitro preparations were used. The effects of 8-OH-DPAT on baseline activity of 91 neurons were tested in the in vivo preparation. In 50/91 cells, 8-OH-DPAT produced a decrease in the firing rate that ranged between 21 and 98% (mean +/- S.E.M. decrease of 49 +/- 1.9%). This inhibitory effect was dose dependent and could be blocked by spiperone. In 10/91 cells, 8-OH-DPAT produced an increase in the firing rate that ranged between 13 and 290%, with mean increase of 83 +/- 7.4%. The baseline firing rate of the remaining 31 cells was not affected by 8-OH-DPAT. In the PAG slice preparation, the effects of 8-OH-DPAT on synaptic and membrane properties of 17 PAG neurons were tested using whole-cell voltage clamp-recording procedures. In 14 cells, application of 8-OH-DPAT produced hyperpolarization that ranged between 6 and 21 mV, with mean of 8.4 +/- 2.0 mV. This hyperpolarization was associated with a decrease in membrane impedance that ranged between 8 and 45%, with mean decrease of 21.6 +/- 4.5%. The remaining three neurons did not respond to 8-OH-DPAT.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of serotonin1A receptors inhibits midbrain periaqueductal gray neurons of the rat. 833 Feb 13

The ontogeny of serotonin receptors in the human brainstem is largely unknown, despite the putative roles of serotonin in neural development, synaptic transmission, brainstem modulation of vegetative functions, and clinical disorders of serotonergic function. This study provides baseline information about the quantitative distribution of [3H]LSD binding to serotonergic receptors (5-HT1A-1D, 5-HT2) in the human brainstem, from midgestation through maturity, with a focus upon early infancy. Brainstems were analyzed from 5 fetuses (19-25.5 weeks postconception), 5 infants (42-55.5 weeks postconception), and 3 mature individuals (4, 20, and 52 years). Tissue autoradiography was used with [3H]LSD for total serotonergic receptor binding and [3H]LSD and serotonin for nonspecific binding; computer-based quantitation was applied. The highest levels of [3H]LSD binding occurred prenatally throughout the brainstem. At all ages, the highest relative binding localized to the rostral raphe. A marked decline in [3H]LSD binding occurred between the midgestation and infancy in brainstem regions involved in control of cardiovascular function, respiration, and pain. The fetal peak in [3H]LSD binding to 5-HT receptors is consistent with a trophic role of serotonin in immature human brainstem, and a decrease, between midgestation and infancy, in serotonergic modulation of vegetative functions controlled by the brainstem.
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PMID:Developmental changes in [3H]lysergic acid diethylamide ([3H]LSD) binding to serotonin receptors in the human brainstem. 855 66

Previous results from our laboratory indicate that serotonin (5-HT) potentiates pain produced by other inflammatory mediators. To characterize the receptor subtype(s) mediating this synergistic effect of 5-HT, selective 5-HT agonists were injected, alone or with noradrenaline (NA) or prostaglandin E2 (PGE2), into the plantar surface of the paws of rats. The behavioural response (favouring, elevation and licking the paw) was recorded using the rating scale developed to quantify formalin-induced pain. The 5-HT1A and 5-HT3 agonists, 8-OH-DPAT and 2-methyl-5-HT, respectively, produced only transient responses by themselves and did not interact with PGE2 or NA. The 5-HT2 agonists, alpha-methyl-5-HT and DOI, also produced transient responses alone, but induced lifting and licking of the injected paw lasting more than 30 min when combined with PGE2 or NA. The lifting and licking response produced by 5-HT plus PGE2 was not altered by intraplantar pretreatment with the 5-HT1A and 5-HT3 antagonists, BMY 7378 and tropisetron, but was attenuated by the 5-HT2A/2C antagonist ketanserin. The pain response produced by alpha-methyl-5-HT plus PGE2 was blocked by pretreatment with the 5-HT2A/2C antagonists ketanserin and ritanserin, and the 5-HT2A antagonist spiperone (MPE50 values 1.4, 7.7 and 0.06 nmol, respectively). The second phase of the response to intraplantar formalin was also attenuated by ketanserin, ritanserin and spiperone (MPE50 values 11.3, 21.8 and 0.23 nmol, respectively). These data imply that 5-HT2A antagonists may be effective peripherally acting analgesics or analgesic adjuncts in pain associated with 5-HT release from platelets, such acute injury and, perhaps, some chronic pain states.
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PMID:Activation of 5-HT2A receptors potentiates pain produced by inflammatory mediators. 868 2

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

In mice injected with formalin into the hindpaw, the 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, equipotently inhibited the early phase (EP) and late phase (LP) of licking. At higher doses, they provoked ataxia and inhibited the writhing elicited by intra-abdominal acetic acid. The antagonists, (-)-alprenolol, (-)-tertatolol, WAY-100,135 and S 15931 were more potent against the LP than the EP. They also inhibited writhing, and only at very high doses did they elicit ataxia. In rats, 8-OH-DPAT and flesinoxan increased the current required to elicit vocalisation upon electrical stimulation of the tail. The action of 8-OH-DPAT was blocked by WAY-100,135, which, like other antagonists, was inactive alone. Interestingly, a low dose of 8-OH-DPAT partially inhibited the antinociceptive action of the mu-opioid agonist, morphine, the action of which was dose-dependently facilitated by (-)-alprenolol and S 15931. Administered s.c., 8-OH-DPAT elicited spontaneous tail-flicks (STFs) in rats: these were abolished by WAY-100,135, (-)-tertatolol, (-)-alprenolol and S 15931. STFs were also eliminated by s.c. or i.t. administration of the alpha 2-adrenergic receptor agonist, clonidine, the GABAA agonist, muscimol or the GABAB agonist, baclofen. The mu-opioid, morphine, blocked STFs only at high doses and the kappa-opioid agonists, U 50,488 and U 69,593, even at supra-ataxic doses, were inactive. Antagonists at neurokinin (NK)1 (RP 67580), NK2 (SR 48,968) and bradykinin (BK)2 (Hoe 140) receptors, as well as aspirin, did not block STFs, though indomethacin was effective. Antagonists at the glycine B site coupled to the NMDA receptor, L 687,414, L 701,324 and (+)-HA966, blocked STFs. Furthermore, (+)-HA 966 and the competitive NMDA receptor antagonist, CPP, were active upon i.t. administration. STFs were also blocked by s.c. or i.t. administration of the AMPA antagonists, YM 900 and NBQX. In conclusion, the influence of 5-HT1A ligands upon nociception is dependent upon the algesiometric paradigm. Intriguingly, modulation of 5-HT1A receptor-mediated STFs reveals parallels to neuropathic pain.
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PMID:Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm. 878 80


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