Dual, Hyperalgesic, and Analgesic Effects of the High-Efficacy 5-Hydroxytryptamine 1A (5-HT<sub>1A</sub>) Agonist F 13640 [(3-Chloro-4-fluoro-phenyl)-[4-fluoro-4-{[(5-methyl-pyridin-2-ylmethyl)-amino]-methyl}piperidin-1-yl]methanone, Fumaric Acid Salt]: Relationship with 5-HT<sub>1A</sub> Receptor Occupancy and Kinetic Parameters

Bardin, Laurent; Assié, Marie Bernadette; Pélissou, Martine; Royer-Urios, Isabelle; Newman‐Tancredi, Adrian; Ribet, Jean‐Paul; Sautel, François; Koek, Wouter; Colpaert, Françis C.

doi:10.1124/jpet.104.077669

Cited by 23 publications

(6 citation statements)

References 36 publications

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“…Male Sprague‐Dawley rats weighing 160–180 g upon arrival were group‐housed (five animals per cage) with free access to food and water. The formalin test was carried out as described by Bardin et al. (2005).…”

Section: Methodsmentioning

confidence: 99%

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Assié

Bardin

et al. 2009

British J Pharmacology

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Background and purpose: Xaliproden (SR57746A) is a 5-HT1A receptor agonist and neurotrophic agent that reduces oxaliplatin-mediated neuropathy in clinical trials. The present study investigated its profile on in vitro transduction, neurochemical responses and acute nociceptive pain tests in rats.Experimental approach: Xaliproden was tested on models associated with 5-HT1A receptor activation including G-protein activation, extracellular dopamine and 5-HT levels measured by microdialysis and formalin-induced pain. Activation of 5-HT1A receptors was confirmed by antagonism with WAY100635. Key results: Xaliproden exhibited high affinity for rat (r) and human (h) 5-HT1A receptors (pKi = 8.84 and 9.00). In [ , p.o. respectively). In rat, it increased extracellular dopamine levels in frontal cortex and reduced hippocampal 5-HT levels (ED50: 1.2 and 0.7 mg·kg -1 , i.p. respectively). In a rat pain model, xaliproden inhibited paw licking and elevation (ED50: 1 and 3 mg·kg -1 , i.p. respectively) following formalin injection in the paw. All effects were reversed by pretreatment with WAY100635. Conclusions and implications:These results indicate that activation of 5-HT1A receptors is the principal mechanism of action of xaliproden and provide further support for the utility of 5-HT1A receptor activation as an anti-nociceptive strategy. Pharmacology (2009) 158, 232-242; doi:10.1111/j.1476-5381.2009 published online 5 June 2009 This article is part of a themed issue on GPCR. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 is a selective and potent 5-HT1A receptor agonist with low nanomolar affinity at 5-HT1A receptors and an efficacy for activating these receptors equivalent to that of (Ϯ)8-OH-DPAT (Bachy et al., 1993;Cervo et al., 1994). In tests predictive of antidepressant properties, including the forced swim and learned helplessness tests, xaliproden reduced immobility scores and increased the duration of escape ('struggling') behaviour, especially when given in a semi-chronic regimen (Simiand et al., 1993;Cervo et al., 1994). Xaliproden is also active in a number of 'anxiolytic-like' activity tests including a Geller-Seifter conflict test, the staircase and the lithium chloride taste aversion models (Simiand et al., 1993). British Journal ofLater studies of xaliproden focused on pro-neurotrophic properties of this compound in cellular models including rat pheochromocytoma PC12 cells (Pradines et al., 1995;Fournier et al., 1998), primary neuronal cells (Ruigt et al., 1996;Fournier et al., 1998;Magazin et al., 1998;Duong et al., 1999), and in animal models of neurodegeneration (Duong et al., 1998;Iwasaki et al., 1998;Lemaire et al., 2002). These studies suggested that these effects of xaliproden were not due to activation of 5-HT1A receptors because other 5-HT1A agonists [buspirone and (Ϯ)8-OH-DPAT] did not share these pro-neurotrophic properties either in vitro (Pradines et al., 1995) or in vivo . However, more recent data suggest that agonism at 5-HT1A receptors ma...

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Section: Methodsmentioning

confidence: 99%

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Assié

Bardin

et al. 2009

British J Pharmacology

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“…It has been shown that 5-HT1A receptor is one of the major subtypes distributed in the dorsal horn of the spinal cord (Lopez-Garcia, 2006). As for the functions of 5-HT1A in the spinal cord dorsal horn, some reports suggest its involvement in mediation of nociception (Zhang et al, 2001; Lindstrom et al, 2009), while others argued for an involvement in anti-nociception of a descending modulatory pathway (Lin et al, 1996; Liu et al, 2002; Bardin et al, 2005; You et al, 2005; Colpaert et al, 2006). By using RT-PCR and Western blot, it was observed that both mRNA and protein levels of 5-HT1A receptors in the ipsilateral dorsal horn could be increased by subcutaneous bee venom injection.…”

Section: Nociceptive and Inflammatory Effects Of Subcutaneous Bee mentioning

confidence: 99%

The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword

Chen

Lariviere

2010

Progress in Neurobiology

166

121

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Bee venom injection as a therapy, like many other complementary and alternative medicine approaches, has been used for thousands of years to attempt to alleviate a range of diseases including arthritis. More recently, additional theraupeutic goals have been added to the list of diseases making this a critical time to evaluate the evidence for the beneficial and adverse effects of bee venom injection. Although reports of pain reduction (analgesic and antinociceptive) and anti-inflammatory effects of bee venom injection are accumulating in the literature, it is common knowledge that bee venom stings are painful and produce inflammation. In addition, a significant number of studies have been performed in the past decade highlighting that injection of bee venom and components of bee venom produce significant signs of pain or nociception, inflammation and many effects at multiple levels of immediate, acute and prolonged pain processes. This report reviews the extensive new data regarding the deleterious effects of bee venom injection in people and animals, our current understanding of the responsible underlying mechanisms and critical venom components, and provides a critical evaluation of reports of the beneficial effects of bee venom injection in people and animals and the proposed underlying mechanisms. Although further studies are required to make firm conclusions, therapeutic bee venom injection may be beneficial for some patients, but may also be harmful. This report highlights key patterns of results, critical shortcomings, and essential areas requiring further study.

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“…The agonists were injected at 3 pharmacologically relevant doses to evaluate the influence of dose on glucose utilization and possible regional preferences of the drugs. The doses of 0.16 mg/kg to 0.63 mg/kg and the route of administration were chosen based on previous preclinical studies. − Each rat was its own control and received each of the three doses of agonist and the saline solution in a randomized order. The interval between two acquisitions was at least 2 days, to ensure complete elimination of the molecules (the plasma half-life of NLX-112 in rat is about 1–2 h).…”

Section: Results and Discussionmentioning

confidence: 99%

Serotonin 5-HT_1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [¹⁸F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats

Levigoureux

Vidal

Fieux

et al. 2018

ACS Chem. Neurosci.

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Serotonin 5-HT 1A receptors constitute an attractive therapeutic target for various psychiatric or neurodegenerative disorders. These receptors are expressed in multiple brain regions on different neuronal populations and can be coupled with distinct G-protein subtypes; such functional diversity complicates the use of 5-HT 1A ligands in several pathologies where it would be desirable to stimulate the receptors in a precise region. Therefore, using "biased agonists" able to target specifically certain subpopulations of 5-HT 1A receptors would enable achievement of better therapeutic benefit. Several 5-HT 1A receptor biased agonists are currently in development, including NLX-101 (aka F15599) and NLX-112 (aka F13640, befiradol), with preclinical data suggesting that they preferentially target different populations of 5-HT 1A receptors. However, most previous studies used invasive and regionally limited approaches. In this context, [ 18 F]-fluorodesoxyglucose (FDG)-positron emission tomography (PET) imaging constitutes an interesting technique as it enables noninvasive mapping of the regional brain activity changes following a pharmacological challenge in conscious animals. We report here the evaluation of cerebral glucose metabolism following intraperitoneal injection of different doses of NLX-112 or NLX-101 in conscious or isofluraneanesthetized rats. The biased agonists produced different metabolic "fingerprints" with distinct regional preferences, consistent with previous studies. At equal doses, the effect of NLX-101 was less marked than NLX-112 in the piriform cortex, in the striatum (in terms of inhibition), and in the pontine nuclei and the cerebellum (in terms of activation); furthermore, only NLX-112 increased the glucose metabolism in the parietal cortex, whereas only NLX-101 induced a clear activation in the colliculi and the frontal cortex, which may be related to its distinctive procognitive profile. Both agonist effects were almost completely unapparent in anesthetized animals, underlining the importance of studying serotonergic neurotransmission in the conscious state. In this regard, [ 18 F]FDG-PET imaging seems very complementary with other functional imaging techniques such as pharmacological MRI.

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Cited by 23 publications

References 36 publications

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword

Serotonin 5-HT_1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [¹⁸F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats

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Cited by 23 publications

References 36 publications

5‐HT1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

5‐HT1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

The nociceptive and anti-nociceptive effects of bee venom injection and therapy: A double-edged sword

Serotonin 5-HT1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [18F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats

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5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

5‐HT_1A receptors are involved in the effects of xaliproden on G‐protein activation, neurotransmitter release and nociception

Serotonin 5-HT_1A Receptor Biased Agonists Induce Different Cerebral Metabolic Responses: A [¹⁸F]-Fluorodesoxyglucose Positron Emission Tomography Study in Conscious and Anesthetized Rats