Effects of PNU-109,291, a selective 5-HT1D receptor agonist, on electrically induced dural plasma extravasation and capsaicin-evoked c-fos immunoreactivity within trigeminal nucleus caudalis

Cutrer, F. Michael; Yu, Xian Jie; Ayata, Gamze; Moskowitz, Michael A.; Waeber, Christian

doi:10.1016/s0028-3908(99)00032-5

Cited by 46 publications

(17 citation statements)

References 48 publications

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“…The source of pain in migraine headache may involve neurogenic plasma extravasation and consequent vascular meningeal inflammation [19,20]. Electrical stimulation of the trigeminal ganglion leads to increases in extracerebral blood flow and local release of both calcitonin gene-related peptide (CGRP) and substance P, both of which are proinflammatory [21].…”

Section: Hypotheses That Might Explain the Link Between Obesity And Mmentioning

confidence: 99%

Obesity and chronic daily headache

Bigal

Lipton

2008

Current Science Inc

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Population studies suggest that obesity is associated with migraine progression from episodic to chronic daily headaches. Although not a risk factor for episodic migraine, obesity is associated with frequent and severe headaches among migraineurs. We suggest that obesity is an exacerbating factor for migraine. This association seems to be specific to migraine and does not apply to tension-type headache. We review the clinical evidence that links obesity and migraine progression. We then review the potential pathophysiologic mechanisms to support this relationship. We close by briefly discussing clinical interventions related to obesity and migraine.

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Section: Hypotheses That Might Explain the Link Between Obesity And Mmentioning

confidence: 99%

Obesity and chronic daily headache

Bigal

Lipton

2008

Current Science Inc

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“…Thus, it can be postulated that the primary mechanism of action for LY334370 is central, that it interrupts the activation of ascending pain pathways and that this action is responsible for its antimigraine effectiveness rather than by the peripheral inhibition of extravasation in the meninges. Another interesting strategy for the treatment of migraine without constrictor side effects is the development of selective 5-HT 1D receptor agonists that block neurogenic dural extravasation in guinea-pigs (Cutrer et al, 1999). On this basis, the selective 5-HT 1D agonist PNU-142633F was tested clinically and demonstrated no efficacy in the treatment of migraine (Cutler et al, 2000;McCall, 1999).…”

Section: Preclinical and Clinical Observations With Selective 5-ht 1dmentioning

confidence: 99%

Neurogenic inflammation in the context of migraine

Williamson

Hargreaves

2001

Microscopy Res & Technique

203

144

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Despite considerable research into the pathogenesis of idiopathic headaches, such as migraine, the pathophysiological mechanisms underlying them remain poorly understood. Although it is well established that the trigeminal nerve becomes activated during migraine, the consequences of this activation remain controversial. One theory, based on preclinical observations, is that activation of trigeminal sensory fibers leads to a painful neurogenic inflammation within the meningeal (dural) vasculature mediated by neuropeptide release from trigeminal sensory fibres and characterized by plasma protein extravasation, vasodilation, and mast cell degranulation. Effective antimigraine agents such as ergots, triptans, opioids, and valproate inhibit preclinical neurogenic dural extravasation, suggesting that this activity may be a predictor of potential clinical efficacy of novel agents. However, several clinical trials with other agents that inhibit this process preclinically have failed to show efficacy in the acute treatment of migraine in man. Alternatively, it has been proposed that painful neurogenic vasodilation of meningeal blood vessels could be a key component of the inflammatory process during migraine headache. This view is supported by the observation that jugular plasma levels of the potent vasodilator, calcitonin gene-related peptide (CGRP) are elevated during the headache and normalized by successful sumatriptan treatment. Preclinically, activation of trigeminal sensory fibers evokes a CGRP-mediated neurogenic dural vasodilation, which is blocked by dihydroergotamine, triptans, and opioids but unaffected by NK1 receptor antagonists that failed in clinical trials. These observations suggest that CGRP release with associated neurogenic dural vasodilation may be important in the generation of migraine pain, a theory that would ultimately be tested by the clinical testing of a CGRP receptor antagonist.

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“…Overall, the modulation of serotonergic neurotransmission via the 1D receptor subtype resulted in only modest effects on rat electroencephalography in our studies. Sumatriptan, a 5-HT1B/1D receptor agonist, PNU-109291, a 5-HT 1D receptor agonist, and BRL15572, a 5-HT 1D receptor antagonist were selected to explore the potential impact of the serotonin 1D receptor on rodent arousal (Kayser et al, 2002; Cutrer et al, 1999; Pauwels & John, 1999). Compound mediated effects on cumulative sleep time and bout duration of REM sleep were specific to BRL 15572, while no significant effects on REM sleep were observed using the nonselective serotonin-1 agonist, sumatriptan.…”

Section: Resultsmentioning

confidence: 99%

“…PNU 109291 is an investigational antimigraine therapy that is a highly selective serotonin-1D receptor agonist (Cutrer et al, 1999). PNU 109291 treatment (10 mg/kg, 15 mg/kg, s.c.) resulted in only minor effects, with no observed trends of treatment on overall rat sleep architecture (Supplemental Figure 6).…”

Section: Resultsmentioning

confidence: 99%

“…In a model of guinea pig hypothermia, BRL-15572 (0.1 and 10 mg/kg), a 5-HT 1D receptor antagonist, did not have an impact on body temperature, but was found to sufficiently penetrate the CNS (Hagan et al, 1997). The 5-HT 1D agonist, PNU-109291 has demonstrated effects in vitro and peripheral effects in vivo , but lacks efficacy in the clinical treatment of migraine (Cutrer et al, 1999; Slassi et al, 2001). PNU-109291 (10 mg/kg and 15 mg/kg, s.c.) was dosed with the understanding that selected doses may not sufficiently cross the blood brain barrier in order to impact arousal.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pharmacological Validation of Candidate Causal Sleep Genes Identified in an N2 Cross

Brunner¹,

Gotter²,

Millstein

et al. 2011

Journal of Neurogenetics

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Despite the substantial impact of sleep disturbances on human health and the many years of study dedicated to understanding sleep pathologies, the underlying genetic mechanisms that govern sleep and wake largely remain unknown. Recently, we completed large scale genetic and gene expression analyses in a segregating inbred mouse cross and identified candidate causal genes that regulate the mammalian sleep-wake cycle, across multiple traits including total sleep time, amounts of REM, non-REM, sleep bout duration and sleep fragmentation. Here we describe a novel approach toward validating candidate causal genes, while also identifying potential targets for sleep-related indications. Select small molecule antagonists and agonists were used to interrogate candidate causal gene function in rodent sleep polysomnography assays to determine impact on overall sleep architecture and to evaluate alignment with associated sleep-wake traits. Significant effects on sleep architecture were observed in validation studies using compounds targeting the muscarinic acetylcholine receptor M3 subunit (Chrm3)(wake promotion), nicotinic acetylcholine receptor alpha4 subunit (Chrna4)(wake promotion), dopamine receptor D5 subunit (Drd5)(sleep induction), serotonin 1D receptor (Htr1d)(altered REM fragmentation), glucagon-like peptide-1 receptor (Glp1r)(light sleep promotion and reduction of deep sleep), and Calcium channel, voltage-dependent, T type, alpha 1I subunit (Cacna1i)(increased bout duration slow wave sleep). Taken together, these results show the complexity of genetic components that regulate sleep-wake traits and highlight the importance of evaluating this complex behavior at a systems level. Pharmacological validation of genetically identified putative targets provides a rapid alternative to generating knock out or transgenic animal models, and may ultimately lead towards new therapeutic opportunities.

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Effects of PNU-109,291, a selective 5-HT1D receptor agonist, on electrically induced dural plasma extravasation and capsaicin-evoked c-fos immunoreactivity within trigeminal nucleus caudalis

Cited by 46 publications

References 48 publications

Obesity and chronic daily headache

Obesity and chronic daily headache

Neurogenic inflammation in the context of migraine

Pharmacological Validation of Candidate Causal Sleep Genes Identified in an N2 Cross

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