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)

Intraperitoneal administration of the serotonin 5-HT1A agonist, buspirone (1-5 mg/kg), produced dose- and time-related core hypothermia that was coincident with analgesia against a thermally noxious stimulus. Surface body temperature was not altered by buspirone. The 5-HT1A antagonist, NAN-190 (2 mg/kg, s.c.), blocked both hypothermic and analgesic effects, while systemic administration of the opioid antagonist, naloxone (1 mg/kg, s.c.), did not change the pattern of buspirone-induced hypothermia or analgesia. The apparent lack of opioid involvement and the documented role of the 5-HT1A receptor system in neuroendocrine substrates of thermoregulation and pain modulation prompted study of adrenal function in these buspirone-induced effects. Buspirone (5 mg/kg, i.p.) produced significant elevations in plasma epinephrine (EPI) and corticosterone (CST). Bilateral adrenalectomy reduced both control and buspirone-elevated EPI and CST levels and attenuated the antinociceptive, but not hypothermic, effects of buspirone (1-5 mg/kg, i.p.). Administration of the phenylethanolamine-N-methyltransferase (PNMT) inhibitor, dichloromethylbenzylamine (DCMB: 25 mg/kg, i.p.) reduced basal and buspirone-elevated plasma EPI, but not CST levels. This treatment did not affect buspirone-induced hypothermia, while significantly reducing buspirone antinociception. Pretreatment with the CST synthesis inhibitor, aminoglutethemide (AG: 2 x 25 mg/kg, i.p.), reduced plasma CST levels while not significantly affecting EPI. AG pretreatment did not alter the hypothermic effects of buspirone, but attenuated antinociception produced by the highest buspirone dose. The AG-induced reductions of buspirone antinociception were less than those effects produced by DCMB treatment. These data suggest that buspirone-induced antinociception may be a non-opioid, adrenally mediated co- and/or epi-phenomenon to core hypothermia evoked by 5-HT1A receptor agonism.
Pain 1992 Sep
PMID:Putative mechanisms of buspirone-induced antinociception in the rat. 145 90

1. The purpose of the present study was to relate the effects of the novel drug, anpirtoline, on 5-hydroxytryptamine (5-HT) receptor subtypes to its antinociceptive and antidepressant-like actions in rodents. 2. Binding assays with rat brain membranes have shown that anpirtoline bound with a much higher affinity to 5-HT1B receptor (Ki = 28 nM) than to 5-HT1A (Ki = 150 nM) and 5-HT2 (Ki = 1.49 microM) receptors. 3. Like 5-HT, anpirtoline concentration-dependently inhibited forskolin-stimulated adenylate cyclase activity in homogenates from the rat substantia nigra. Both effects were not additive, and could be prevented by 5-HT1B receptor antagonists such as propranolol and penbutolol. 4. In superfused rat and pig brain cortex slices preincubated with [3H]-5-HT, the electrically evoked tritium overflow was inhibited by anpirtoline and 5-HT. Whereas 5-HT was equipotent in both tissues (EC50 = 69 nM), anpirtoline was markedly less potent in pig brain cortex slices (EC50 = 1190 nM) than in rat brain cortex slices (EC50 = 55 nM). The concentration-response curve for anpirtoline was shifted to the right by metitepine in both preparations. 5. In the social behaviour deficit test, anpirtoline and trifluoromethylphenyl-piperazine were effective in reversing the isolation-induced impairments in mice, an effect shown only by compounds with agonist properties at the 5-HT1B receptor. 6. In the electrostimulated pain test using mice, anpirtoline dose-dependently increased the pain threshold with an ED50 of 0.52 mg kg-1, i.p. The antinociceptive activity of anpirtoline was abolished by pretreatment with cyproheptadine or propranolol.7. In the forced swimming test in rats, anpirtoline induced a dose-related increase in swimming activity. With an ED50 value of 4.6mgkg-1, i.p., anpirtoline was 4 times more potent than the two standard compounds imipramine and desipramine. The decrease of immobility time or the increase of active periods in this model of behavioural despair is suggested to be characteristic of antidepressant drugs.8. Anpirtoline exhibits both antinociceptive and antidepressant-like activities in animals. It is probable that anpirtoline elicits these pharmacological effects via its agonist effect on 5-HT1B and 5-HT1A receptors.
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PMID:Anpirtoline, a novel, highly potent 5-HT1B receptor agonist with antinociceptive/antidepressant-like actions in rodents. 162 59

The effects of a number of 5-HT receptor ligands were examined on nonopioid defensive analgesia in male DBA/2 mice. MDL 73005EF (0.05-1.0 mg/kg), a selective 5-HT1A receptor agonist, potently and dose-dependently inhibited the analgesic consequences of social defeat. CGS 12066B (0.5-10.0 mg/kg) and MK-212 (0.3-10.0 mg/kg), selective agonists for 5-HT1B and 5-HT1C sites, respectively, failed to influence this particular form of adaptive pain inhibition. Two 5-HT2/1C receptor antagonists, ritanserin (0.05-10.0 mg/kg) and ICI 169.369 (0.3-10.0 mg/kg), were also devoid of specific effects upon defensive analgesia. Both ritanserin and ICI 169,369 were found to have intrinsic analgetic efficacy and to induce behavioural changes indicative of increased defensiveness. These data, together with previous findings, confirm the specific involvement of 5-HT1A receptor mechanisms in the analgesic consequences of social defeat in male mice. Results are discussed in relation to the role of anxiety in adaptive pain inhibition.
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PMID:Differential effects of novel ligands for 5-HT receptor subtypes on nonopioid defensive analgesia in male mice. 179 10

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.
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PMID:Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat. 201 33

The 5-HT1A partial agonists, buspirone, ipsapirone and gepirone did not affect the latency to respond in the tail flick test to heat. However, they strongly attenuated the antinociceptive action of the mu-opioids, morphine and sufentanil. The buspirone metabolite, 1-(2-pyrimidyl)pyridine (1-PP) was ineffective. BMY 7378, spiperone and alprenolol, putative antagonists at 5-HT1A sites, did not modify basal latencies or the action of morphine. TFMPP and mCPP, agonists at 5-HT1B and 5-HT1C sites, also did not affect basal latencies or morphine induced antinociception. These data show that 5-HT1A partial agonists attenuate morphine-evoked antinociception without affecting basal thresholds. They represent an interesting aspect of the interaction between opioids and serotonin in the control of nociception. In addition to opioids (Millan, 1986), serotonin (5-HT) is considered to play a major role in the control of pain and in the expression of opioid analgesia (Roberts, 1984). The identification of a multiplicity of binding sites for 5-HT in the CNS (Fozard, 1987) raises the question of their individual roles in nociceptive processes. The 5-HT1A site is of particular interest since it is present in high concentrations in the dorsal horn of the spinal cord (Daval, Verge, Basbaum, Bourgoin, and Hamon, 1987) and there are conflicting reports that it may mediate analgesia or hyperalgesia (Berge, Fasmer, Ogren, and Hole, 1985, Zemlan, Kow, and Pfaff, 1983). Indeed, the 5-HT1A agonist, 8-OH-DPAT, was reported to attenuate morphine-evoked antinociception in mice (Berge et al., 1985).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Attenuation of opioid induced antinociception by 5-HT1A partial agonists in the rat. 213 88

We have recently shown the serotonin 5-HT1A receptor agonist buspirone to produce analgesia in several pain tests in rats. As a 5-HT1A agonist, buspirone may change serotonergic (5-HT) tone to alter the balance of central monoaminergic (MA) systems that function in analgesia. MA-reuptake blocking drugs have been shown to produce analgesia, both when given alone and in combination with a variety of other agents, presumably via their action upon MA neurochemistry. The present study was undertaken to examine the effect of systemic administration of the 5-HT-reuptake blocker amitriptyline (AMI: 10 mg/kg), NE-reuptake blocker desipramine (DMI: 10 mg/kg) or DA-reuptake blocker GBR-12909 (7.5 mg/kg) on patterns of analgesia produced by buspirone (1-5 mg/kg) in thermal and mechanical pain tests in rats. Neither reuptake blocking agents or buspirone, when administered alone or in combination, produced overt changes in motor activity at the doses tested. AMI alone was not analgesic in either thermal or mechanical pain tests. In both assays, AMI reduced the analgesic action of buspirone, with greater effects seen in the thermal test. When administered alone, DMI produced significant analgesia against thermal and mechanical pain. DMI significantly attenuated the analgesic action of all doses of buspirone in both pain tests. Alone, GBR-12909 did not affect nociception in thermal or mechanical tests. GBR-12909 decreased buspirone-induced analgesia at all doses in the thermal test, while having no effect on buspirone-induced analgesia against mechanical pain. These results demonstrate that facilitation of 5-HT, NE and DA function with reuptake blocking drugs did not enhance the analgesic action of buspirone. These data indicate against the adjuvant use of reuptake blocking compounds and buspirone as analgesics. Furthermore, such findings may suggest other possible non-MA substrates of buspirone-induced analgesia.
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PMID:Effects of systemically administered monoamine reuptake blocking agents on patterns of buspirone-induced analgesia in rats. 214 89

Because a satisfactory animal model for migraine does not exist, attempts to determine a common mechanism of action for effective antimigraine agents may be of benefit in elucidating the pathogenesis of this neurologic syndrome. The present review demonstrates that the clinical data that has developed over the past 30 years may allow for the elucidation of the role of specific 5-HT receptor subtypes in the pathophysiology of migraine. A large number of both acute and prophylactic antimigraine agents share an ability to interact with 5-HT receptor subtypes in human brain. As summarized in Table 3, acute antimigraine drugs (e.g., ergots, sumatriptan) share high affinity for 5-HTID receptors and somewhat lower affinity for 5-HT1A receptors. These receptors are present in certain intracranial blood vessels. 5-HT1D receptors are also located on nerve terminals where they act to inhibit the release of 5-HT and other neurotransmitters. Theoretically, 5-HTID receptor agonists may acutely inhibit the release of vasoactive or pain-inducing substances in the perivascular space. Conceivably, drugs acting at this receptor would stop the progression of this perivascular process. In addition, a number of prophylactic antimigraine drugs display a relatively high affinity for both 5-HT2 and 5-HT1C receptors in human brain. Although these receptors are also found in certain blood vessels, they are present throughout the nervous system. The receptors appear to mediate neuronal depolarizations at the cellular level. Moreover, the 5-HT2 receptor appears to play a key role in the development of inflammation in certain smooth muscle systems. Theoretically, the ability of 5-HT2 antagonists to protect perivascular inflammation may account for their efficacy in the prophylactic treatment of migraine. These data offer a novel approach to the analysis of antimigraine agents. Drugs could be selected for use in clinical migraine studies based on their selectivity for a specific 5-HT receptor subtype. For example, an agent that displays both high affinity and selectivity for 5-HT1D receptors could be clinically evaluated. Its effectiveness, or lack thereof, would indicate the importance of this specific 5-HT receptor site in the pathogenesis of migraine. Future attempts to determine a common mechanism of action for effective antimigraine agents should facilitate the elucidation of the pathogenesis of this neurologic syndrome.
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PMID:Developments in 5-hydroxytryptamine receptor pharmacology in migraine. 225 14

Recent studies have suggested that anxiety may be an important factor in the non-opioid analgesic response to defeat in muroid rodents. In the present study, we have examined the influence of the 5-HT1A receptor agonist, 8-OH-DPAT, on basal nociception and defeat analgesia in male DBA/2 mice. Our results show that, while devoid of intrinsic activity on the mouse tail-flick assay, 8-OH-DPAT blocks the analgetic consequences of defeat. A ten-fold potency differential was observed as a function of route of injection, with minimum effective doses of 0.1 and 1.0 mg/kg for subcutaneous and intraperitoneal administration, respectively. Although further studies are required, these preliminary data support 5-HT1A receptor involvement in the mediation of this form of adaptive pain inhibition.
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PMID:5HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), inhibits non-opioid analgesia in defeated mice: influence of route of administration. 252 55

Behavioural and pharmacological studies have suggested that anxiety may be an important factor in the initiation of non-opioid analgesia in defeated male mice. In the present study, the effects of three 5-HT1A anxiolytics (buspirone, ipsapirone and gepirone) on basal nociception and defeat analgesia were examined. Results show that the analgesic consequences of social defeat were potently blocked by all three compounds, with a rank-order potency (minimum effective doses) of ipsapirone (0.05 mg/kg) greater than gepirone (0.1 mg/kg) greater than buspirone (0.5 mg/kg). These inhibitory effects on defeat analgesia were observed in the absence of intrinsic activity on basal nociception (tail-flick assay). When administered alone, (-)pindolol produced biphasic effects on defeat analgesia with enhancement at 0.5 mg/kg and inhibition at 5.0 mg/kg. Lower doses of (-)pindolol (0.05 and 0.25 mg/kg) which did not affect defeat analgesia when administered alone, totally blocked the inhibitory effects of ipsapirone (0.5 mg/kg). Data are discussed in relation to the involvement of 5-HT1A receptor mechanisms in this adaptive form of pain inhibition.
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PMID:Prevention of the analgesic consequences of social defeat in male mice by 5-HT1A anxiolytics, buspirone, gepirone and ipsapirone. 257 79

Here we describe the potent antinociceptive action of the indolophenanthridine, CY 208-243, which has high affinities to the dopamine D1 binding and the opioid sites as well as to the 5-HT1A site. The antinociceptive action was comparable to that of morphine in most, but not all models of nociception, nevertheless, basic differences exist in its overall profile. Antagonism of CY 208-243's antinociceptive action was only possible with either high doses of naloxone or not at all and no cross-tolerance with morphine in CY 208-243 tolerant rats occurred. The biochemical basis for dependence liability may be absent and no opioid activity was observed in cultured hippocampal cells. Physical dependence did not occur after programmed administration in the rhesus monkey, nor did CY 208-243 cause respiratory depression in the rat (rather a stimulation). Lack of generalization in fentanyl-trained rats strongly suggests that CY 208-243 lacks opioid-like subjective cues. The coexistence of D1 dopaminergic and atypical opioid agonist properties represents a unique pharmacodynamic combination which is not shared with any other analgesic, and may provide safe and innovative pain therapy.
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PMID:CY 208-243: a unique combination of atypical opioid antinociception and D1 dopaminomimetic properties. 282 54


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