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PubMed1993

Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms.

The effects of neocortical spreading depression (SD) on the expression of immunoreactive c-fos protein were examined within the superficial laminae of trigeminal nucleus caudalis (TNC), a brainstem region processing nociceptive information. KCl was microinjected into the left parietal cortex at 9 min intervals over 1 hr, and SD was detected by a shift in interstitial DC potential within adjacent frontal cortex. The stained cells in lower brainstem and upper cervical spinal cord were counted on both sides after tissues were sectioned (50 microns) and processed for c-fos protein-like immunoreactivity (LI) using a rabbit polyclonal antiserum. C-fos protein-LI was visualized in the ventrolateral TNC, chiefly in laminae I and Ilo and predominantly within spinal segment C1-2 (e.g., -1.5 to -4.5 mm from obex) ipsilaterally. SD significantly increased cell staining within ipsilateral TNC. The ratio of cells in laminae I and Ilo on the left: right sides was 1.32 +/- 0.13 after 1 M KCl, as compared to 1.06 +/- 0.05 in control animals receiving 1 M NaCl instead of KCl microinjections (p < 0.01). The ratio was reduced to an insignificant difference after chronic surgical transection of meningeal afferents and recurrent SD (1.09 +/- 0.11). Pretreatment with intravenous sumatriptan, a 5-HT1-like receptor agonist that selectively blocks meningeal C-fibers and attenuates c-fos protein-LI within TNC after noxious meningeal stimulation, also reduced the ratio to an insignificant difference (1.10 +/- 0.09). Sumatriptan or chronic surgical transection of meningeal afferents, however, did not reduce the ability of KCl microinjections to induce SD. On the other hand, combined hyperoxia and hypercapnia not only reduced the number of evoked SDs from 6.3 +/- 1.0 to 2.5 +/- 1.2 after 0.15 M KCl microinjection, but also significantly (p < 0.01) reduced associated c-fos protein-LI in TNC. These data indicate that multiple neocortical SDs activate cells within TNC. The increase in c-fos protein-LI, observed predominantly ipsilaterally, was probably mediated by SD-induced stimulation of ipsilaterally projecting unmyelinated C-fibers innervating the meninges. If true, this is the first report demonstrating that neurophysiological events within cerebral cortex can activate brainstem regions involved in the processing of nociceptive information via trigeminovascular mechanisms.

Afferent Pathways↗
PubMed1993

Neurogenic inflammation in the pathophysiology and treatment of migraine.

The trigeminal nerve transmits headache pain from blood vessels of the pia mater and dura mater. Triggers for this pain are not well understood, but probably are multiple and largely chemical and develop within the brain parenchyma, the blood vessel wall, and the blood itself. These unknown triggers stimulate the trigeminovascular axons, causing pain and releasing vasoactive neuropeptides from perivascular axons. Released neuropeptides activate endothelial cells, mast cells, and platelets to then increase extracellular levels of amines, arachidonate metabolites, peptides, and ions. Hyperalgesia and prolongation of pain develop as a consequence, mediated by products from activated cells and injured tissue. Within postsynaptic brain stem neurons of the trigeminal nucleus caudalis, trigeminovascular activation stimulates the expression of an early immediate response gene c-fos. Both neurogenic inflammation and c-fos expression are blocked by sumatriptan and ergot alkaloids via prejunctional mechanisms involving putative 5-HT receptors closely related to the 5-HT1D subtype on trigeminovascular fibers. The mechanisms of action of sumatriptan and ergot alkaloids described herein are unrelated to the nature of the migraine trigger or to the contractile state of vascular smooth muscle.

Blood Proteins↗
PubMed1997

Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation.

We have investigated the control of calcitonin gene-related peptide (CGRP) expression by a serotonergic agonist that is related pharmacologically to currently used antimigraine drugs. During migraines, CGRP levels are elevated but then returned to normal by a 5-HT1 receptor agonist, sumatriptan. However, neither the molecular nor cellular targets of this drug are known. Trigeminal neurons are the major source of cerebrovascular CGRP, and thus we have used trigeminal primary cultures and the neuronal-like CA77 thyroid C-cell line as a model. We first demonstrate that sumatriptan and another 5-HT1 agonist, CGS 12066A (CGS), cause a robust and prolonged increase with oscillations in intracellular calcium in CA77 cells. CGS caused a similar increase in trigeminal cultures. We then show that CGS treatment leads to a decrease in CGRP mRNA levels in the CA77 cells. This decrease is attributable to the repression of promoter activity through two discrete elements: (1) the cAMP-responsive region, via a cAMP-independent mechanism; and (2) the cell-specific enhancer, which binds the upstream stimulatory factor helix-loop-helix protein and a cell-specific activator. These results demonstrate that activation of the endogenous 5-HT1 receptor is coupled to calcium signaling pathways and leads to inhibition of CGRP gene transcription.

Animals↗
PubMed1997

Technetium-99m-HMPAO, technetium-99m-ECD and iodine-123-IMP cerebral blood flow measurements with pharmacological interventions in primates.

UNLABELLED: Technetium-99m-bicisate ethyl cysteinate dimer (ECD) presents a different pattern from cerebral blood flow (CBF) in the subacute phase of cerebral infarction, as measured by PET, perhaps due to lack of oxygen and enzyme activity; this pattern is contrary to that of hexamethyl-propyleneamine oxime (HMPAO) but similar to that of N-isopropyl-[123I]beta-iodoamphetamine ([123I]IMP). This study explores possible CBF differences among HMPAO, ECD and IMP, with various relevant drug interventions. METHODS: Anesthetized adult baboons were used in these SPECT studies. Four studies (n = 6 baboons for each study), one control study and three intervention studies involving intravenous acetazolamide, nimodipine infusion and intramuscular sumatriptan, were followed with 99mTc-HMPAO, 99mTc-ECD and [123I]IMP. The split-dose method was used as follows. For each tracer, intervention data from the second SPECT (SPECT-2) after the second tracer injection (444 MBq) reflected a change in CBF with respect to the baseline SPECT (SPECT-1) data from the initial injection (222 MBq). These changes as a ratio, R (R = SPECT-2/SPECT-1), for each study, and the R values for each tracer were compared to R values from the corresponding control studies, yielding a quantitative estimate of drug effects. RESULTS: There were no significant differences (p > 0.05) between HMPAO and ECD for the control, acetazolamide and sumatriptan studies, but there was indeed a difference between the two for the nimodipine study, indicating a nimodipine-dependent underestimation of CBF with ECD (and also with IMP), with respect to HMPAO. A further significant difference was that larger CBF increases were observed with acetazolamide, as measured with [123I]IMP. CONCLUSION: This is a crucial observation for the clinical interpretation of CBF SPECT data and should direct the choice of tracer for a specific examination.

Acetazolamide↗
PubMed1998

Serotonin in migraine: theories, animal models and emerging therapies.

A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.

Animals↗
PubMed1993

5-Hydroxytryptamine (5-HT) contracts the guinea-pig isolated iliac artery via 5-HT1-like and 5-HT2 receptors.

The characterization of 5-hydroxytryptamine (5-HT) receptors mediating contractions of the guinea-pig isolated iliac artery was studied when the basal tone was slightly increased by prostaglandin F2 alpha (PGF2 alpha). In the presence of ketanserin (1 mumol/l), 5-HT and several 5-HT receptor agonists induced contractile responses with the rank order of agonist potency: 5-HT = 5-carboxyamidotryptamine (5-CT) = lysergol > ergometrine = methylergometrine > RU 24969 approximately 5-methoxytryptamine (5-MeOT) > methysergide > sumatriptan > tryptamine. Concentration-effect curves to the ergot alkaloids, lysergol, ergometrine, methylergometrine and methylsergide, were biphasic. In the presence of ketanserin (1 mumol/l), contractile responses to 5-HT, 5-CT, RU 24969, 5-MeOT, sumatriptan and tryptamine were antagonized by methiothepin (30 nmol/l) and flesinoxan (3 mumol/l) with approximate pKB values of 8.5-9.0 and 6.0-6.3, respectively. The first phase of contraction produced by the ergot alkaloids, lysergol, ergometrine, methylergometrine and methysergide, were blocked by methiothepin (30 nmol/l) and flesinoxan (3 mumol/l), respectively, with approximate pKB values about 8.4-8.7 and 6.2-6.4, respectively. The mechanism underlying the second phase of contraction remains to be established. Maximum responses of the concentration-effect curves to 5-HT (1 nmol/l-1 mumol/l) were concentration-dependently depressed by ketanserin (1 nmol/l-1 mumol) and spiperone (30 nmol/l-0.3 mumol/l) and reached approximately 60% of the 5-HT maximum response in the presence of ketanserin (1 mumol/l) and spiperone (0.1 mumol/l), respectively. Agonist potency of 5-HT was not affected by the antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

5-Hydroxytryptamine receptors with a 5-HT6 receptor-like profile stimulating adenylyl cyclase activity in pig caudate membranes.

This study deals with the characterization of 5-hydroxytryptamine (5-HT, serotonin) receptors positively linked to adenylyl cyclase in membranes from pig brain caudate. 5-HT and related agonists induced a concentration-dependent stimulation of adenylyl cyclase activity in pig caudate membranes, with the following rank order of potency (mean pEC50 values): 5-HT (7.1) > or = 5-methoxytryptamine (6.9) > 5-carboxamidotryptamine (5.6) > sumatriptan (< 5). Maximal stimulation by 5-HT averaged 35 pmol cyclic AMP/min/mg protein over a basal activity of 159 pmol cyclic AMP/min/mg protein. 5-Methoxytryptamine and 5-carboxamidotryptamine had similar efficacies to that of 5-HT, whereas sumatriptan was about half efficacious. Other compounds known as agonists at some 5-HT receptors were weakly potent (mean pEC50 values < 5). They include the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), the 5-HT4 receptor agonist, renzapride and the 5-HT2 receptor agonist, (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane) (DOI). In antagonist studies, methiothepin (0.1 and 1 mumol/l) shifted the 5-HT curve to the right with no depression of the Emax, yielding pKB values of 7.4-8.0. Clozapine (1 mumol/l) also produced surmountable antagonism of 5-HT-induced effects (pKB 6.9). Ketanserin (10 mumol/l) weakly antagonized 5-HT (pKB 5.0). The 5-HT4 receptor antagonists, tropisetron (ICS 205-930) and SDZ 205-557 (2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester), each at 1 mumol/l, did not significantly alter the concentration-response curve of 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1998

Porcine carotid vascular effects of eletriptan (UK-116,044): a new 5-HT1B/1D receptor agonist with anti-migraine activity.

It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine. Indeed, a number of acutely acting anti-migraine drugs, including the ergot alkaloids and sumatriptan, constrict porcine carotid arteriovenous anastomoses. In this study, using pentobarbital anaesthetised pigs, we investigated the effects of eletriptan, a close structural analogue of sumatriptan, on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient (capillary) fractions. Eletriptan (10, 30, 100, 300 and 1000 microg kg(-1), i.v.) decreased the total carotid blood flow, exclusively by decreasing cephalic arteriovenous anastomotic blood flow; nutrient blood flow, particularly to the ear, skin and fat, was significantly increased. The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50% (ED50) were, respectively, 117+/-21 microg kg(-1) (251+/-45 nmol kg(-1)) and 184+/-42 microg kg(-1) (396+/-91 nmol kg(-1)); the highest dose caused reductions of 84+/-3% and 77+/-4%, respectively. The eletriptan-induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective 5-HT1B/1D receptor antagonist GR127935 (0.5 mg kg(-1)). On the basis of these results, we conclude that (1) the eletriptan-induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by 5-HT1B/1D receptors, and (2) eletriptan should be effective in aborting migraine headache. Clinical studies have already demonstrated its therapeutic action in migraine patients.

Animals↗
PubMed2000

5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes: further evidence using 5-HT moduline, polyclonal 5-HT1B receptor antibodies and 5-HT1B receptor knock-out mice.

In previous paper based on classical pharmacological tools, we identified a Gi protein-coupled presynaptic 5-hydroxytryptamine (5-HT) 1B receptor causing inhibition of dopamine (DA) release in rat striatal synaptosomes. It was the aim of the present study to further explore this receptor, using 5-HT moduline, a polyclonal antibody directed against 5-HT1B receptors and 5-HT1B receptor knock-out mice. Preincubation of rat striatal synaptosomes with 5-HT moduline (0.1, 1, or 10 microM) significantly reduced the inhibitory effect of CP93,129, a selective rat 5-HT1B receptor agonist, on K+-evoked overflow of [3H]DA in a non-competitive manner: 5-HT moduline did not modify the IC50 of CP93,129, but concentration-dependently reduced the maximal inhibitory effect. Preincubation of rat striatal synaptosomes with a specific polyclonal 5-HT1B receptor antibody also resulted in a significant attenuation of the inhibitory effect of CP93,129 on K+-evoked overflow of [3H]DA. In female 129/Sv wild-type mice, CP93,129 and 5-carboxyamidotryptamine maleate (5-CT), a non-selective 5-HT1B receptor agonist, inhibited the K+-evoked [3H]DA overflow in a concentration-dependent manner. Sumatriptan, a selective rat 5-HT1D receptor agonist, did not modify the overflow of [3H]DA. SB224289, a selective 5-HT1B receptor antagonist, abolished the inhibitory effects of CP93,129 and 5-CT. The inhibitory effects of CP93,129 and 5-CT were absent in synaptosomes from 5-HT1B receptor knockout mice. No compensatory inhibition effect in mutant mice was observed using sumatriptan. In conclusion, the results show that a non-competitive antagonist of the 5-HT1B receptor concentration-dependently decreases the maximal inhibitory effect of a 5-HT1B receptor agonist on the synaptosomal K+-evoked release of [3H]DA in striatum. Moreover, a specific antibody raised against the receptor and particularly directed against a region of the receptor protein involved in signal transduction, namely the coupling with the G-protein, also antagonizes the inhibitory effect of the stimulation of 5-HT1B receptor on the release of [3H]DA. Ultimately the disruption of 5-HT1B receptor gene in 5-HT1B knock-out mice leads to a total suppression of the effect of 5-HT1B receptor agonists on [3H]DA release. These observations further support our previous observations using selective agonists/antagonists, indicating that 5-HT1B receptors control the release of neuronal DA as presynaptic heteroreceptors.

Amino Acid Sequence↗
PubMed2005

The use of multiattribute decision models in evaluating triptan treatment options in migraine.

BACKGROUND: The physician treating patients with migraine is now able to choose from among seven triptans-almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. These differ, to greater or lesser degrees, on a range of clinical attributes important for treatment selection. OBJECTIVE: To outline the basic principles of Multiattribute Decision Making (MADM) and describe how one such method-TOPSIS (Technique for Order Preference by Similarity to the Ideal Solution)-can be applied to evaluate the currently available triptans. METHODS: In an example application, summary data from a recent meta-analysis of 53 published and unpublished placebo-controlled trials of the oral triptans were combined in TOPSIS models with computer-generated attribute importance weights representing the entire range of possible values, That is, the relative performance of the triptans was explored across all logically possible combinations of relative importance of the treatment attributes available from the meta-analysis, and uncertainty was assessed based on the confidence intervals from the meta-analysis. RESULTS: When compared across the entire range of values for relative attribute importance, almotriptan, eletriptan and rizatriptan were more similar to a hypothetical ideal triptan and were more likely to appear in the top three closest to the hypothetical ideal, than were naratriptan, sumatriptan, and zolmitriptan. CONCLUSION: Using the TOPSIS model, almotriptan, eletriptan and rizatriptan were more likely to appear in the top three closest to the hypothetical ideal triptan.

Clinical Trials as Topic↗
PubMed1999

[Postdural puncture headache: diagnosis, prevention and therapy].

Lumbar puncture (LP) is a routine technique performed for a variety of procedures, e.g. diagnosis, administration of drugs, myelography and spinal anaesthesia. Postdural puncture headache is a common complication (30-40% in diagnostic LP). Prevention can be accomplished by using small-gauge needles (< or = 25 G) or pencil-point needles (22 G). Therapy should be carried out in a stepwise approach. The first step is bedrest, use of analgetics, i.v. fluids and an adequate guidance of the patient. The second step comprises special drug therapy. Several methods of pharmacologic management have been presented in the literature, but most of these are case reports. There is a lack of large double-blind placebo-controlled studies. Theophylline, caffeine, ACTH and sumatriptan are potentially promising agents for the treatment of postdural puncture headache. The efficacy of theophylline has been proven in a double-blind and placebo-controlled study. There are a few studies and case reports reporting that caffeine p.o. and i.v. is effective in the treatment of postdural puncture headache, but recurrence of headache after caffeine therapy is frequent. ACTH acts on a complex hormonal system. The treatment with sumatriptan has been reported in only a few case reports. The third step, and one of the most effective treatments of postdural puncture headache, is the epidural blood patch. The success rate ranges between 80 and 97%.

English Abstract↗
PubMed2006

Great occipital nerve blockade for cluster headache in the emergency department: case report.

A 44-year-old man with a past medical history of episodic cluster headache presented in our ED with complaints of multiple daily cluster headache attacks, with cervico-occipital spreading of pain from May to September 2004. The neurological examination showed no abnormalities as well as brain and spine MRI. Great Occipital Nerve (GON) blockade, with Lidocaine 2% (5 ml) and betamethasone (2 mg), were performed in the right occipital region (ipsilaterally to cluster headache), during attack. GON blockade was effective immediately for the attack and the cluster period resolved after the injection. We suppose that the action of GON blockade may involve the trigemino-cervical complex and we moreover strongly suggest to use GON blockade in emergency departments for cluster headache with cervico-occipital spreading as attack abortive therapy, especially in oxygen and sumatriptan resistant cluster headache attacks, in patients who complaints sumatriptan side-effects or have contraindications to use triptans.

Adult↗
PubMed1999

Cluster Headache.

The care of patients with cluster headache has at least two goals: 1) immediately abolishing an ongoing attack and 2) stopping or shortening a bout (a cluster period). The fierceness and the relative brevity of the attacks dictate the use of a fast-acting agent. There are probably three agents fulfilling these criteria: sumatriptan (by subcutaneous injection), oxygen (inhaled through a face mask), and ergotamines (by injection or, perhaps, sublingual tablets). An abundance of data from controlled studies as well as recent clinical experience probably favors sumatriptan as the most effective alternative, the most significant drawback being its high cost. Oxygen inhalation is free of side effects and may be effective but is inconvenient to use. Ergotamines in tablet form act less rapidly, and there are more contraindications to their use. In short-term prophylaxis, however, ergotamine may still be a drug of choice if the timing of the attacks allows planned use of the drug shortly before the attack. If the timing is more irregular, steroids may at least temporarily break a cycle (eg, prednisolone, 60 or 80 mg/d, gradually tapered to zero in 3 to 4 weeks). If more long-lasting prophylaxis is needed or expected, lithium carbonate, 900 mg/d, or verapamil, 360 mg/d, both have reasonable response rates. As for chronic cluster headache, lithium probably will still be the drug of choice. For a very limited group of patients with chronic cluster headache, surgery may be a last resort. The best surgical options are probably radiofrequency rhizotomy or microvascular decompression of the trigeminal nerve.

Journal Article↗
PubMed1990

5-HT1-like receptors mediate contractions of the rabbit saphenous vein.

5-Hydroxytryptamine (5-HT) elicited concentration-dependent contractions of the rabbit isolated saphenous vein. The effects of 5-HT were mimicked by 5-carboxamidotryptamine (5-CT), 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) and sumatriptan; the rank order of potency (pD2 values) was 5-CT (7.6) greater than 5-HT (6.9) greater than 8-OH-DPAT (6.2) greater than RU 24969 (6.1) greater than sumatriptan (5.7). The maximal response to RU 24969 was less than that to the other compounds, implying that RU 24969 may behave as a partial agonist. Methiothepin (10(-8), 3 x 10(-8) and 3 x 10(-7) M), ketanserin (10(-7), 3 x 10(-7) and 10(-6) M) and spiperone (10(-7), 10(-6) and 10(-5) M), but not 1 alpha H,3 alpha,5 alpha H- tropan-3-yl-3,5-dichlorobenzoate (MDL 72222; 10(-7), 10(-6) or 10(-6) M), cyanopindolol (10(-7) and 10(-6) M) or propranolol (10(-7) and 10(-6) M), shifted the concentration-effect curve of 5-HT to the right in a concentration-dependent manner with pA2 values of 8.25, 7.51 and 6.12, respectively. The high activity of 5-CT and methiothepin compared to, respectively, 5-HT and ketanserin (and spiperone) suggests that the contraction of the rabbit saphenous vein is not mediated by 5-HT2 receptors. The receptor involved seems to be mainly 5-HT1-like, similar to the one mediating contraction of the dog saphenous vein, human basilar artery and porcine cranial arteriovenous anastomoses.

Animals↗
PubMed1992

Heterogeneity of contractile 5-HT receptors in human hand veins.

To increase our knowledge of human peripheral vasospasm we characterized the contractile 5-hydroxytryptamine (5-HT) receptors in human superficial hand vein segments in vitro. The 5-HT1 receptor agonist, sumatriptan, the 5-HT2 receptor agonist, dl-alpha-methyl-5-HT, and the 5-HT3 receptor agonist, 2-methyl-5-HT, all induced concentration-dependent contractions. The contractile response to sumatriptan was antagonized by the non-selective 5-HT receptor antagonist, methiothepin, but was unaffected by the 5-HT2 receptor antagonist, ketanserin. The contractile response to dl-alpha-methyl-5-HT was antagonized by both methiothepin and ketanserin. The contraction elicited by 2-methyl-5-HT was not affected by the 5-HT3 receptor antagonist, MDL 72222, but was antagonized by ketanserin. The results suggest that serotonergic contraction in the human superficial hand vein involves both 5-HT1 and 5-HT2 but not 5-HT3 receptors. Such receptor heterogeneity in human blood vessels should be considered when using drugs and when designing future compounds for medical use.

Adult↗
PubMed1992

Evidence that 5-HT2 receptors predominantly mediate the contraction of the rat basilar artery to 5-hydroxytryptamine.

We characterised the 5-hydroxytryptamine (5-HT) receptor subtype which mediates the contraction of the rat isolated basilar artery, mounted in a myograph, by using agonists and antagonists for 5-HT1-like, 5-HT2, 5-HT3 and 5-HT4 receptors. The rank order of potency for a range of selective agonists was: 5-HT > alpha-methyl-5-HT > 5-carboxamidotryptamine > 2-methyl-5-HT > sumatriptan. The maximum contractions for these agonists (Emax) was less than for 5-HT while 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was devoid of contractile activity. Ketanserin antagonised the contractile effect of 5-HT in the rat basilar artery with a provisional pA2 estimate of 9.3 +/- 0.2. A similar antagonism was observed against alpha-methyl-5-HT. Ergometrine (0.01-1 microM) was devoid of any agonist activity but antagonised the contractile effect of 5-HT on the rat basilar artery with a provisional pKB of 8.7 (7.8-9.8, 95% confidence limits). The 5-HT3 and 5-HT4 receptor antagonist ICS 205930 (10 microM) did not alter the response to 5-HT. The high potency and efficacy of alpha-methyl-5-HT, poor effect of sumatriptan and antagonism of 5-HT by ergometrine and ketanserin, support the conclusion that the 5-HT2 receptors are primarily responsible for the 5-HT-induced contraction of rat basilar artery.

Animals↗
PubMed1995

Novel 5-HT2-like receptor mediates neurogenic relaxation of the guinea-pig proximal colon.

The aim of the current investigation was to characterize the 5-HT receptors that mediate neurogenic relaxation of the guinea-pig proximal colon. After blockade of 5-HT2A, 5-HT3 and 5-HT4 receptor-mediated contractions, 5-hydroxytryptamine (5-HT) induced relaxations yielding a biphasic concentration-response curve. Other tryptamines were also agonists with the following rank order of potency: 5-HT > 5-carboxamidotryptamine = 5-methoxytryptamine > or = alpha-methyl-5-HT (partial agonist) > tryptamine (partial agonist). 5-Hydroxytryptophan, 2-methyl-5-HT and N-methyltryptamine were virtually inactive as agonists. The curve to 5-HT was not affected by pargyline, citalopram, phentolamine, or by the 5-HT4 receptor antagonists 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205-557) and (1-butyl-4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan+ ++-5-carboxylate (SB 204070). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), 5-methoxy-3[1,2,3,6-tetrahydroxypyridin-4-yl]-1H-indole (RU 24969), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), 1-(3-chlorophenyl)piperazine (mCPP), 1-(m-trifluoromethylphenyl)-piperazine (TFMPP), flesinoxan, sumatriptan and 6-chloro-2-(piperazinyl)-pyrazine (MK212) were inactive as 5-HT receptor agonists. The first phase of the curve to 5-HT was inhibited by: metergoline (pA2 = 8.8 +/- 0.3, against 5-methoxytryptamine 9.3 +/- 0.3), methysergide (non-surmountable), methiothepin (non-surmountable), spiroxatrine (non-surmountable), MK212 (non-surmountable), mesulergine (7.8 +/- 0.3), mCPP (7.1 +/- 0.1), mianserin (7.0 +/- 0.4), ritanserin (8.9 +/- 0.2), rauwolscine (7.0 +/- 0.2), yohimbine (6.2 +/- 0.2), 1-(1-naphthyl)-piperazine (7.7 +/- 0.2) and RU 24969 (6.4 +/- 0.1), but not by 1-(2-methoxyphenyl)4-[4-(2-phthalimidobtyl]-piperazine (NAN-190), spiperone, sumatriptan, 8-OH-DPAT and flesinoxan. It is suggested that the 5-HT receptor under study could be considered an unknown 5-HT2-like receptor.

Animals↗
PubMed1995

Autoradiographic visualisation of [3H]5-carboxamidotryptamine binding sites in the guinea pig and rat brain.

We have investigated the distribution of [3H]5-carboxamidotryptamine ([3H]5-CT) binding sites by in vitro autoradiography on sections of guinea-pig and rat brain. In saturation studies, the ligand recognised a saturable, homogeneous population of binding sites with an affinity ranging from 0.19-0.45 nM depending on the region. The labelling pattern was heterogeneous, and the displacement pattern with different competing drugs selective for different 5-HT receptor subtypes was complex. [3H]5-CT appeared to label 5-HT1B/5-HT1D sites in the substantia nigra, globus pallidus and caudate/putamen, as the binding in these regions was displaced by the 5-HT1B/1D receptor selective agents sumatriptan, CP-122,288 and GR-127,935. In the hippocampus and lateral septum, the very dense [3H]5-CT binding was displaced with high affinity by the 5-HT1A receptor selective agonist 8-hydroxy-dipropylaminotetralin ((+/-)-8-OH-DPAT), dihydroergotamine and 5-HT. In contrast the affinity of the 5-HT1 receptor antagonists spiperone and methiothepine was much lower than their previously published potency at 5-HT1A receptors. The affinity of agonists, taken together with the fact that the distribution of these [3H]5-CT sites overlaps that of [3H]8-OH-DPAT binding sites in serial sections, suggest that these sites correspond to 5-HT1A receptors. Their atypical properties deserve further investigations. While [3H]5-CT binding at 5-HT1B/1D sites and these atypical 5-HT1A sites was inhibited by the GTP analogue 5'-beta, gamma-imidotriphosphate, [3H]5-CT binding in the superficial cortical layers and in midline thalamic nuclei was insensitive to this agent. It was however displaced by low concentrations of spiperone, clozapine and methiothepine, but not by sumatriptan, CP-122,288, GR-127,935 or dihydroergotamine. This binding profile is similar to that of 5-HT7 receptors, while the spatial distribution of these sites matches the known distribution of 5-HT7 messenger RNA. We did not find evidence of [3H]5-CT labelling to 5-HT5 receptors, in spite of their reported high affinity for this ligand. It is concluded that [3H]5-CT, in the presence of selective blockers, can be used to investigate the properties of 5-HT1A, 5-HT1B/1D and 5-HT7 receptors in the rodent brain, although further studies are required to explain the atypical features of [3H]5-CT binding in 5-HT1A receptors containing regions.

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