François Giuliano

Neural control of erection.

Activation of sacral parasympathetic pathways elicits penile erection through the release of vasorelaxant neurotransmitters that increase blood flow to the penis and relax the penile erectile tissue. Sympathetic pathways are antierectile. The pudendal pathway, responsible for the contraction of the perineal striated muscles, enhances an already present erection. All pathways originate in the spinal cord, but at various levels and areas. The convergence of information from peripheral and supra-spinal origins onto spinal neurones is very likely activating more specifically the spinal pro-erectile network. Peripheral information is the afferent limb of reflexive erections, impinges onto spinal interneurones and is able to activate or regulate the activity of sympathetic, parasympathetic and somatic nuclei. Supra-spinal information impinges onto either the same or a different spinal network. Premotor neurones located in supra-spinal structures, that project directly onto spinal sympathetic, parasympathetic or pudendal motoneurones, are present in the medulla, pons and diencephalon. Several of these premotor neurones may in turn be activated by sensory information from the genitals. Descending pathways release a variety of aminergic and peptidergic neurotransmitters in the vicinity of spinal neurones, thereby exerting complex effects on the spinal pro-erectile network. Brainstem and hypothalamic nuclei (among the latter, the paraventricular nucleus and the medial preoptic area) may not reach directly the spinal pro-erectile network. They are prone to regulate penile erection in more integrated and coordinated responses of the body, as those occurring during sexual behaviour. The pro-erectile central and spinal effects of neuropeptides such as oxytocin, melanocortins and endorphins have only recently been analyzed. Such compounds may represent therapeutic strategies to treat erectile dysfunction through a central site of action.

Central neurophysiology and dopaminergic control of ejaculation

Although premature ejaculation (PE) represents the most common male sexual dysfunction, brain mechanisms controlling ejaculatory process remain poorly understood. Recently a group of neurons, identified in the lumbar spinal cord, has been proposed to constitute a spinal ejaculation generator. This key site in ejaculation control, relaying sensory inputs to the brain, is under supraspinal excitatory (medial preoptic area, paraventricular nucleus of the hypothalamus) and inhibitory (nucleus paragigantocellularis) controls. Activation of brain excitatory areas by dopamine (DA) or DA agonists being demonstrated to facilitate ejaculation, it seems particularly interesting to further understand the implication of central DA in the complex process leading to ejaculation. Moreover, the fact that dopaminergic pathways are involved in sexual behavior and that DA release in some brain regions is an important facilitator of male sexual behavior reinforces the crucial implication of DA. Clearly, a better understanding of DA incerto-hypothalamic pathways and targeting brain DA receptor subtypes mediating ejaculation (especially D(3) receptors) will benefit the development of new pharmacological strategies to treat ejaculatory dysfunction including PE.

Spinal control of penile erection

SummarySmooth muscle relaxation of penile arteries, the corpus cavernosum, and the corpus spongiosum, leading to penile erection, results from parasympathetic neural pathway activation and, likely, simultaneous inhibition of sympathetic outflow. Proerectile parasympathetic outflow is reflexively activated by sensory information of peripheral origin, conveyed by the dorsal penile nerve, and reflexive erections are supported by an intraspinal circuitry. Supraspinal influences modulate the reflex. Information integrated at or originating from supraspinal structures may also elicit penile erection. Several neurotransmitters are involved in either the modulation of the spinal reflex or the mediation of supraspinal influences. Spinal cord injury differently alters reflexive penile erection or erection from a central origin, depending on the neurologic level of injury.

A comparison of the effects of tamsulosin and alfuzosin on neurally evoked increases in bladder neck and seminal vesicle pressure in rats

To assess the effects of the α1‐adrenoceptor antagonists alfuzosin and tamsulosin on the physiological events associated with ejaculation in the rat, because when these drugs are used for treating symptomatic benign prostatic hyperplasia in men they may affect ejaculation by impairing bladder neck closure and seminal vesicle contraction.

Ejaculation induced by I.C.V. injection of the preferential dopamine D3 receptor agonist 7-hydroxy-2-(Di-N-propylamino)tetralin in anesthetized rats

In addition to serotonin, dopamine within the CNS is known to play a primary role in the control of ejaculation. However, whether D(2) and/or D(3) dopamine receptor subtypes mediate this effect is still unclear. In order to clarify this issue, a pharmacological competitive study using the preferential D(3) agonist 7-hydroxy-2-(di-N-propylamino)tetralin (7-OH-DPAT) alone or in combination with competitive nonpreferential or preferential D(2) and D(3) antagonists delivered intracerebroventricularly (i.c.v.) was undertaken in anesthetized rats. Urethane-anesthetized male rats were implanted into the cerebral ventricle with a cannula for i.c.v. injections, and recording electrodes were placed within the bulbospongiosus (BS) muscle to monitor BS muscle contractions, which were used as a marker for the expulsion phase of ejaculation. Following i.c.v. injection, 7-OH-DPAT induced ejaculation and rhythmic BS muscle contractions. Co-injected i.c.v. with 7-OH-DPAT, the nonselective D(2)/D(3) antagonist (raclopride), and the preferential D(3) antagonist (S(-)-N[n-butyl-2-pyrrolidinyl)methyl]-1-methoxy-4-cyanonaphtalene-2-carboxamide; nafadotride) but not the preferential D(2) antagonist ((+/-)-3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole; L 741,626) inhibited the occurrence of ejaculation and BS muscle contractions. These results suggest that i.c.v. delivery of 7-OH-DPAT does represent a pertinent model to investigate the physio-pharmacology of ejaculation. It is inferred that targeting brain D(3) receptors may provide a therapeutic approach for treating ejaculatory disorders in humans.

The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat

Melanocortins have been reported to play a role in the control of both male and female sexual behavior. The present study examined the effects of melanotan-II (MT-II), a cyclic peptide analogue of alpha-melanocyte stimulating hormone on appetitive and consummatory aspects of female sexual behavior, including aspects of sexual proceptivity (solicitations, hops and darts, ear wiggling, pacing) and receptivity (lordosis). One group of ovariectomized Long-Evans rats (n=7) was primed subcutaneously with estradiol benzoate (EB) and progesterone (P) (10 microg and 500 microg respectively) and another group (n=7) with EB (10 microg) and oil (EB alone). Paced mating tests were performed with sexually experienced males in unilevel chambers, which were bisected by a Plexiglas divider containing three holes, through which only the female could pass. MT-II (1 and 3 mg/kg) or saline was injected intravenously 10 min before each 30-min paced mating test. Each female received the 3 treatments. In females primed with EB+P both doses of MT-II increased the number of hops and darts and ear wiggling significantly, but did not alter pacing or lordosis. With EB alone, no effect of MT-II was observed on any of the parameters measured. These results suggest that P can interact with MT-II to increase proceptive behaviors. Because hops and darts are essentially solicitations, made in close proximity to the male, that indicate a desire on the part of females to receive mounts and intromissions, these data suggest that activation of melanocortin receptors may represent a promising mode of action for the treatment of women with hypoactive sexual desire.

Microinjection of the preferential dopamine receptor D3 agonist 7-hydroxy-N,N-di-N-propylaminotetralin hydrobromide into the hypothalamic medial preoptic area induced ejaculation in anesthetized rats

The pivotal role of the medial preoptic area (MPOA) of the hypothalamus in the dopaminergic cerebral control of ejaculation has been investigated for years; nevertheless the function of different dopamine receptors subclasses and their exact interrelations merit additional research. One hundred nanograms of a preferential D(3) agonist 7-OH-DPAT (7-hydroxy-N,N-di-n-propylaminotetralin hydrobromide) was microinjected unilaterally into the MPOA of male rats anesthetized with urethane. An ejaculation-related response (bulbospongiosus muscles rhythmic contractions and/or seminal vesicle pressure increases and/or expulsion of a semen plug) was observed in 8 of 10 rats devoid of sexual stimuli, while a similar response was observed in only one rat administered with 10 ng of 7-OH-DPAT. The effect of 7-OH-DPAT 100 ng was mostly abolished by simultaneous MPOA microinjection of 300 ng of a preferential D(3) antagonist N-[(n-butyl-2-pyrrolidinyl) methyl]-1-methoxy-4-cyanonaphthalene-2-carboxamide tartrate (nafadotride). Our results support the hypothesis that supraspinal command of ejaculation is mediated by D(2)-like receptors, probably by D(3) receptors, in the MPOA, and draw attention to the idea of these receptors serving as a promising target for pharmacological treatment of human ejaculatory disorders.

Comparison between tamsulosin and alfuzosin on the expulsion phase of ejaculation in rats

To investigate the effects of acute intravenous (i.v.) delivery of tamsulosin and alfuzosin on the contractions of bulbospongiosus muscles (BS) induced by central delivery of a serotonin agonist, 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), in anaesthetized rats, as an experimental model of the expulsion phase of ejaculation.

Piboserod (SB 207266), a selective 5-HT4 receptor antagonist, reduces serotonin potentiation of neurally-mediated contractile responses of human detrusor muscle

The aim of this study is to evaluate the potency of piboserod (SB 207266), a selective 5-HT4 receptor antagonist, at inhibiting the 5-HT4-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500xa0mg and EFS (20xa0Hz, 1xa0ms duration at 300xa0mA for 5xa0s) was applied continuously at 1xa0min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1xa0nM–100xa0μM) were constructed in the absence or presence of 1 or 100xa0nM of piboserod. The experiments were performed in the presence of methysergide (1xa0μM) and ondansetron (3xa0μM) to block 5HT1/5HT2 and 5-HT3 receptors, respectively. 5-HT potentiated the contractile responses to EFS of human bladder strips in a concentration-dependent manner, with a maximum mean of 60.0±19.9% of the basal EFS-evoked contractions. Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100xa0nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0±7.9 and 38.7±8.7%, respectively. A mean apparent antagonist dissociation constant value (KB) of 0.56±0.09xa0nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. Therefore, the 5-HT4 receptor might represent an attractive pharmacological target for the treatment of overactive bladder.

Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat.

The effects of melanotan-II, a non-specific agonist of melanocortin receptors, on erection and its possible sites of action were investigated in anesthetized rats. Delivered i.v. (0.1, 0.3 and 1 mg/kg) or within the paraventricular nucleus of the hypothalamus (0.1 and 1 microg), melanotan-II exerted a dose-dependent inducer activity on erection by eliciting erectile events and shortening latency of the first erectile event to occur. Erectile events were of higher amplitude in rats treated with melanotan-II i.t. (0.2 microg) delivered at the L6-S1 level than in animals treated with the vehicle i.t. delivered. Erectile responses elicited by cavernous nerve stimulation were increased after i.v. melanotan-II (1 mg/kg), thereby exerting facilitator effect on erection. In contrast, melanotan-II injected within the corpus cavernosum (1 microg) did not display any facilitator activity. To investigate the neural pathways involved in the facilitator effect of melanotan-II, we performed acute spinalization (T8 level) and differential selective nerve transections. Neither spinalization nor bilateral transection of pelvic nerves or dorsal penile nerves impaired facilitator activity of i.v. melanotan-II (1 mg/kg). Conversely, the facilitator effect of melanotan-II was abolished after acute removal of the lumbar paravertebral sympathetic chain. These results lead to the conclusion that central and peripheral melanocortin pathways are recruited by melanotan-II, depending on its route of delivery, to exert both inducer and facilitator activities on erection.