Pelvipharm Laboratories

Orsay, France

Pelvipharm Laboratories

Orsay, France
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Clement P.,Pelvipharm Laboratories | Clement P.,University of Versailles | Bernabe J.,Pelvipharm Laboratories | Bernabe J.,University of Versailles | And 7 more authors.
British Journal of Pharmacology | Year: 2013

Background and Purpose Oxytocin (OT) plays a major role in the control of male sexual responses. Notably, blockade of OT receptors has been reported to inhibit ejaculation in animals. The study aimed to investigate the action of a highly selective, non-peptide OT antagonist GSK557296 in a model of pharmacologically induced ejaculation in anaesthetized rats. The site of action was assessed by investigating different delivery routes for this compound. Experimental Approach Urethane-anaesthetized Wistar rats were implanted with a cerebral ventricle cannula for i.c.v. injections or with a subdural catheter for intrathecal (i.t.) GSK557296 injections. Occurrence of ejaculation was assessed following i.v. 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT), a dopamine D3 receptor agonist. In addition, seminal vesicle pressures (SVP) and bulbospongiosus muscle (BS) EMG were recorded as physiological markers of emission and expulsion phases of ejaculation respectively. Key Results Highest i.v. GSK557296 dose reduced occurrence of ejaculation and increases in SVP but had no effect on BS-EMG. I.c.v. GSK557296 dose dependently inhibited ejaculation, increases in SVP and BS contractions. At spinal thoracic level, GSK557296 dose dependently inhibited ejaculation and increases in SVP but BS-EMG was impaired only with the highest dose. When delivered at lumbar level, GSK557296 dose dependently inhibited ejaculation, increases in SVP and BS contractions. Conclusions and Implications In the 7-OH-DPAT-induced ejaculation model, GSK557296 acts peripherally and centrally to inhibit ejaculation with different modalities. Blockade of brain OT receptors seems to be the most effective mechanism of action. Targeting central OT receptors with highly selective antagonist seems a promising approach for the treatment of premature ejaculation. © 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.


Gelez H.,Pelvipharm Laboratories | Poirier S.,Pelvipharm Laboratories | Allers K.A.,Boehringer Ingelheim | Wayman C.,Pfizer | And 3 more authors.
Journal of Sexual Medicine | Year: 2010

Introduction.: The clitoris and the vagina are the main peripheral anatomical structures involved in physiological changes related to sexual arousal and orgasm. Their efferent control and, more particularly, the neurochemical phenotype of these descending neuronal pathways remain largely uncharacterized. Aim.: To examine if brain neurons involved in the efferent control of the clitoris and the vagina possess melanocortin-4 receptor (MC4-R) and/or contain oxytocin (OT). Methods.: Neurons involved in the efferent control of the vagina and clitoris were identified following visualization of pseudorabies virus (PRV) retrograde tracing. PRV was injected into the vagina and clitoris in adult rats in estrous. On the fifth day postinjection, animals were humanely sacrificed, and brains were removed and sectioned, and processed for PRV visualization. The neurochemical phenotype of PRV-positive neurons was identified using double or triple immunocytochemical labeling against PRV, MC4-R, and OT. Double and triple labeling were quantified using confocal laser scanning microscopy. Main Outcome Measure.: Neuroanatomical brain distribution, number and percentage of double-labeled PRV/MC4-R and PRV-/OT-positive neurons, and triple PRV-/MC4-R-/OT-labeled neurons. Results.: The majority of PRV immunopositive neurons which also expressed immunoreactivity for MC4-R were located in the paraventricular and arcuate nuclei of the hypothalamus. The majority of PRV positive neurons which were immunoreactive (IR) for OT were located in the paraventricular nucleus (PVN), medial preoptic area (MPOA), and lateral hypothalamus. PRV positive neurons were more likely to be IR for MC4-R than for OT. Scattered triple-labeled PRV/MC4-R/OT neurons were detected in the MPOA and the PVN. Conclusion.: These data strongly suggest that MC4-R and, to a less extent, OT are involved in the efferent neuronal control of the clitoris and vagina, and consequently facilitate our understanding of how the melanocortinergic pathway regulates female sexual function. © 2010 International Society for Sexual Medicine.


Chehensse C.,University of Versailles | Clement P.,University of Versailles | Clement P.,Pelvipharm Laboratories | Joussain C.,University of Versailles | And 5 more authors.
Neuroscience | Year: 2016

The inability to ejaculate, i.e. anejaculation, affects the vast majority of men after spinal cord injury (SCI). Ejaculation can however be obtained in approximately half of SCI men by applying extraphysiological vibratory stimulation to the penis suggesting that a spinal neural organization commanding ejaculation exists than can be activated despite disruption of cerebral connections. In the rat, a spinal generator of ejaculation (SGE) has been identified which is notably characterized by the presence of substance P (SP) receptor (neurokinin-1 receptor) onto the constituting neurons. The aim of this study was to evaluate the consequence of chronic spinal cord section and the effect of SP on the function of the rat SGE. Electrical stimulations of varying intensity were applied to SGE in anesthetized rats 4 weeks after complete transection of the thoracic spinal cord (T9) and ejaculation occurrence as well as peripheral responses, i.e. bulbospongiosus electromyogram and pressure within the seminal vesicle, were monitored. Then the effect of SP locally delivered was assessed in this experimental setting. Occurrence of ejaculation elicited by SGE stimulation, SGE excitatory threshold, and amplitude of peripheral responses were unchanged in spinalized as compared to spinally intact rats. In spinalized rats, SP triggered ejaculation upon intraspinal delivery into the SGE area and decreased the SGE stimulation intensity provoking ejaculation after intrathecal administration indicating a decrease in SGE excitatory threshold. The pro-ejaculatory inducing and facilitating effects of SP were reversed by the selective neurokinin-1 receptor antagonist RP67580. It was concluded that chronic spinalization has no significant impact on SGE functioning and SP exerts a pro-ejaculatory role at the SGE level, opening new avenues for the treatment of anejaculation in SCI men. © 2016 IBRO


Fernandez I.G.,Antonio Narro Agrarian Autonomous University | Luna-Orozco J.R.,Antonio Narro Agrarian Autonomous University | Vielma J.,Antonio Narro Agrarian Autonomous University | Duarte G.,Antonio Narro Agrarian Autonomous University | And 4 more authors.
Hormones and Behavior | Year: 2011

We investigated whether LH secretion, estrous behavior and fertility would differ between sexually inexperienced and experienced anestrous goats exposed to the males. Male goats were rendered sexually active during the reproductive rest season by exposure to 2.5. months of artificial long days. Two groups of anovulatory sexually inexperienced and sexually experienced does were exposed to males during 15 days (n = 20 per group). LH pulsatility was determined every 15 min from 4 h before to 8 h after introducing males (Day 0). Estrous behavior was recorded twice daily. Pregnancy rates were determined on Day 50. Fertility was determined at parturition. Male sexual behavior was registered on days 1 and 2 during 1 h. Before introducing the males, the number of LH pulses did not differ between groups. After introduction of the males, all females increased their LH pulsatility, but the number of pulses did not differ between sexually inexperienced and experienced goats. The proportion of females displaying estrous behavior with a high pregnancy rate and fertility did not differ between inexperienced and experienced goats. The sexual behavior of the males did not differ significantly between those interacting with sexually inexperienced or experienced goats. We conclude that goats can show substantial endocrine and reproductive responses to males, even in the absence of previous sexual experience, when sexually active bucks are used. © 2011 Elsevier Inc.


Delgadillo J.A.,Antonio Narro Agrarian Autonomous University | Vielma J.,Antonio Narro Agrarian Autonomous University | Hernandez H.,Antonio Narro Agrarian Autonomous University | Flores J.A.,Antonio Narro Agrarian Autonomous University | And 4 more authors.
Hormones and Behavior | Year: 2012

We investigated whether live vocalizations emitted by bucks interacting with anestrous females stimulate secretion of LH, estrous behavior and ovulation in anestrous goats. In experiment 1, bucks rendered sexually active by exposure to long days followed by natural photoperiod were exposed in a light-proof-building to five anestrous females. Buck vocalizations were reproduced through a microphone-amplifier-loudspeaker system to an open pen where one group of goats (n = 6) was exposed for 10 days to these live vocalizations. Another group of females (n = 6) was isolated from males and vocalizations. The proportion of goats displaying estrous behavior was significantly higher in females exposed to buck vocalizations than in females isolated from males. The proportion of goats that ovulated did not differ between the 2 groups (exposed to males versus isolated). In experiment 2, female goats that either had previous contact with males (n = 7), or no previous contact with males (n = 7) were exposed to live buck vocalizations, reproduced as described in experiment 1, for 5 days. The number and amplitude of LH pulses did not differ between groups before exposition to buck vocalizations. Five days of exposure to male vocalizations significantly increased LH pulsatility only in females that had previous contact with males, while LH pulse amplitude was not modified. We concluded that live buck vocalizations can stimulate estrous behavior and LH secretion in goats if they have had previous contact with bucks. © 2012 Elsevier Inc.


Giuliano F.,Raymond Poincare Hospital | Giuliano F.,Pelvipharm Laboratories | Giuliano F.,University of Versailles | Clcment P.,Pelvipharm Laboratories | Clcment P.,University of Versailles
Pharmacological Reviews | Year: 2012

Male sexual response comprises four phases: excitement, including erection; plateau; ejaculation, usually accompanied by orgasm; and resolution. Ejaculation is a complex sexual response involving a sequential process consisting of two phases: emission and expulsion. Ejaculation, which is basically a spinal reflex, requires a tight coordination between sympathetic, parasympathetic, and somatic efferent pathways originating from different segments and area in the spinal cord and innervating pelviperineal anatomical structures. A major relaying and synchronizing role is played by a group of lumbar neurons described as the spinal generator of ejaculation. Excitatory and inhibitory influences from sensory genital and cerebral stimuli are integrated and processed in the spinal cord. Premature ejaculation (PE) can be defined by <1-min ejaculatory latency, an inability to delay ejaculation, and negative personal consequences. Because there is no physiological impairment in PE, any pharmacological agent with central or peripheral mechanism of action that is delaying the ejaculation is a drug candidate for the treatment of PE. Ejaculation is centrally mediated by a variety of neurotransmitter systems, involving especially serotonin and serotonergic pathways but also dopaminergic and oxytocinergic systems. Pharmacological delay of ejaculation can be achieved either by inhibiting excitatory or reinforcing inhibitory pathways from the brain or the periphery to the spinal cord. PE can be treated with long-term use of selective serotoninreuptake inhibitors (SSRIs) or tricyclic antidepressants. Dapoxetine, a short-acting SSRI, is the first treatment registered for the on-demand treatment of PE. Anesthetics applied on the glans penis have the ability to lengthen the time to ejaculation. Targeting oxytocinergic, neurokinin-1, dopaminergic, and opioid receptors represent future avenues to delaying ejaculation. © 2012 by The American Society for Pharmacology and Experimental Therapeutics.


Gelez H.,Pelvipharm Laboratories | Poirier S.,Pelvipharm Laboratories | Facchinetti P.,French Institute of Health and Medical Research | Allers K.A.,Boehringer Ingelheim | And 5 more authors.
Journal of Chemical Neuroanatomy | Year: 2010

The melanocortin-4 receptor (MC4-R) plays a critical role in several physiological functions, from food intake, energy homeostasis, neuroendocrine and cardiovascular function, to sexual responses. The brain regions and the central neuronal pathways mediating the different actions of MC4-R remain largely unknown. We aimed to use immunocytochemistry using a specific antibody against rat MC4-R, to establish the detailed neuroanatomical distribution of MC4-R in brain slices of male and estrous female rats. We demonstrated that MC4-R-positive neurons were widely distributed in several brain regions including the cortex, thalamus, hypothalamus, and brainstem. In both male and female brains, MC4-R-positive cells were especially abundant in the hypothalamus, including the paraventricular hypothalamic nucleus, lateral septal nucleus, arcuate nucleus, supraoptic nucleus, medial preoptic area and lateral hypothalamic area. A moderate number of MC4-R-positive neurons were found in the piriform cortex, bed nucleus of the stria terminalis, medial and basolateral nuclei of amygdala, periaqueductal gray, red nucleus and raphe nucleus. A dimorphic sexual difference in the number of MC4-R-positive neurons was observed in some brain regions. In the medial preoptic area and arcuate nucleus, MC4-R-positive neurons were significantly more abundant in female than in males, whereas in the lateral hypothalamus the opposite proportion was observed. This is the first time the neuroanatomical distribution, and sex differences, of brain MC4-R localisation have been described. The distribution of MC4-R is consistent with the proposed roles of MC4-R-positive neurons and provides further information about the circuitry controlling food intake, energy balance and sexual responses in both males and females. © 2010 Elsevier B.V.


Clement P.,Pelvipharm Laboratories | Clement P.,University of Versailles | Laurin M.,Pelvipharm Laboratories | Laurin M.,University of Versailles | And 9 more authors.
Journal of Sexual Medicine | Year: 2012

Introduction. A brain network specifically activated when ejaculation occurs has been described in rats. Increasing serotonin (5-hydroxytryptamine [5-HT]) tone impairs ejaculation and chronic 5-HT selective serotonin reuptake inhibitors (SSRIs) are known to inhibit ejaculation. However, efficacy of acute treatment with SSRI varies from one compound to another. The SSRI dapoxetine has been reported to delay ejaculation when given on demand to men with premature ejaculation (PE), although the mechanism of action is unclear. Effects of acute SSRIs on activity of the brain ejaculation circuit in relation with ejaculation have never been examined. Aim. To test the effects of acute administration of the short half-life SSRI dapoxetine on ejaculatory performance and activity in brain ejaculation circuit in rapid ejaculator rats taken as PE model. Methods. Standard copulatory test was used to attribute one sexual category (sluggish, middle, or rapid) to male rats on the basis of their ejaculatory performance. Parameters of sexual, including ejaculatory, behavior, and Fos level of expression in discrete brain areas were assessed in the three sexual categories and in rapid category following acute oral treatment with dapoxetine. Main Outcome Measures. Ejaculation frequency (EF) and latency (EL) were measured as primary end points of ejaculatory behavior. Density of Fos-immunopositive cells in specific brain areas of brain stem, hypothalamus, and thalamus was determined as marker of neuronal activity. Results. EL and Fos level of expression in hypothalamic and thalamic structures were found related. Dapoxetine acute oral administration (300mg/kg) to rapid ejaculator rats resulted in (i) diminution of ejaculatory performance (lengthened EL and decreased EF); and (ii) modulation of Fos level of expression in hypothalamic and thalamic nuclei of the brain ejaculatory circuit. Conclusion. Acute treatment with dapoxetine, which reduced ejaculatory performance in rapid ejaculator rats, was also accompanied with changes in neuronal activity in components of the brain ejaculatory network. © 2012 International Society for Sexual Medicine.


Facchinetti P.,University of Versailles | Giuliano F.,University of Versailles | Giuliano F.,Pelvipharm Laboratories | Giuliano F.,Raymond Poincare Hospital | And 6 more authors.
Neuroscience | Year: 2014

A spinal generator for ejaculation (SGE) has been identified in the rat that orchestrates peripheral events leading to ejaculation. Despite physiological evidence of cerebral influences exerted on the SGE, brain-descending pathways to the SGE have not been fully delineated. A tracing study combining retrograde and anterograde approaches was undertaken in adult male rats in order to identify brain sites containing neurons that directly project onto SGE neurons. Fluorogold (FG) was microinjected as a retrograde tracer into the SGE area in the central medial gray of the third lumbar (L3) spinal segment. FG-positive neurons were found in various structures in medulla oblongata, pons, and forebrain. Among the brain structures already known as participating in the brain control of ejaculation and harboring retrogradelly-labeled neurons, the ventrolateral part of the gigantocellular nucleus and the raphe pallidus/magnus in medulla oblongata as well as the lateral hypothalamus were targeted with the anterograde tracer dextran amine (DA). Galanin and substance P receptor (NK1) were used as markers of SGE neurons. DA-positive fibers and varicosities originating in the targeted brain sites were found to make close appositions with neurons expressing galanin or NK1 receptors in central medial gray of L3-L4 spinal segments. This study provides new insights regarding the anatomical support for the brain control of ejaculation via direct influences onto the SGE. © 2014 IBRO.


PubMed | Pelvipharm Laboratories
Type: Journal Article | Journal: The journal of sexual medicine | Year: 2012

A brain network specifically activated when ejaculation occurs has been described in rats. Increasing serotonin (5-hydroxytryptamine [5-HT]) tone impairs ejaculation and chronic 5-HT selective serotonin reuptake inhibitors (SSRIs) are known to inhibit ejaculation. However, efficacy of acute treatment with SSRI varies from one compound to another. The SSRI dapoxetine has been reported to delay ejaculation when given on demand to men with premature ejaculation (PE), although the mechanism of action is unclear. Effects of acute SSRIs on activity of the brain ejaculation circuit in relation with ejaculation have never been examined.To test the effects of acute administration of the short half-life SSRI dapoxetine on ejaculatory performance and activity in brain ejaculation circuit in rapid ejaculator rats taken as PE model.Standard copulatory test was used to attribute one sexual category (sluggish, middle, or rapid) to male rats on the basis of their ejaculatory performance. Parameters of sexual, including ejaculatory, behavior, and Fos level of expression in discrete brain areas were assessed in the three sexual categories and in rapid category following acute oral treatment with dapoxetine.Ejaculation frequency (EF) and latency (EL) were measured as primary end points of ejaculatory behavior. Density of Fos-immunopositive cells in specific brain areas of brain stem, hypothalamus, and thalamus was determined as marker of neuronal activity.EL and Fos level of expression in hypothalamic and thalamic structures were found related. Dapoxetine acute oral administration (300 mg/kg) to rapid ejaculator rats resulted in (i) diminution of ejaculatory performance (lengthened EL and decreased EF); and (ii) modulation of Fos level of expression in hypothalamic and thalamic nuclei of the brain ejaculatory circuit.Acute treatment with dapoxetine, which reduced ejaculatory performance in rapid ejaculator rats, was also accompanied with changes in neuronal activity in components of the brain ejaculatory network.

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