Olivier Rampin

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.

Oxytocinergic innervation of autonomic nuclei controlling penile erection in the rat

In the rat, spinal autonomic neurons controlling penile erection receive descending pathways that modulate their activity. The paraventricular nucleus of the hypothalamus contributes oxytocinergic fibers to the dorsal horn and preganglionic sympathetic and parasympathetic cell columns. We used retrograde tracing techniques with pseudorabies virus combined with immunohistochemistry against oxytocin and radioligand binding detection of oxytocinergic receptors to evidence the oxytocinergic innervation of thoracolumbar and lumbosacral spinal neurons controlling penile erection. Spinal neurons labelled with pseudo-rabies virus transsynaptically transported from the corpus cavernosum were present in the intermediolateral cell column and the dorsal gray commissure of the thoracolumbar and lumbosacral spinal cord. Confocal laser scanning microscopic observation of the same preparations revealed close appositions between oxytocinergic varicosities and pseudorabies virus-infected neurons, suggesting strongly the presence of synaptic contacts. Electron microscopy confirmed this hypothesis. Oxytocin binding sites were present in the superficial layers of the dorsal horn, the dorsal gray commissure and the intermediolateral cell column in both the thoracolumbar and lumbosacral segments. In rats, stimulation of the paraventricular nucleus induces penile erection, but the link between the nucleus and penile innervation remains unknown. Our findings support the hypothesis that oxytocin, released by descending paraventriculo-spinal pathways, activates proerectile spinal neurons.

Oxytocinergic and serotonergic innervation of identified lumbosacral nuclei controlling penile erection in the male rat

Penile erection is due to activation of proerectile neurons located in the sacral parasympathetic nucleus of the L6-S1 spinal cord in the rat. Contraction of the ischiocavernosus and bulbospongiosus striated muscles, controlled by motoneurons located in the ventral horn of the L5-L6 spinal cord, reinforces penile erection. Physiological and pharmacological arguments have been provided for a role of oxytocin and serotonin in the spinal regulation of penile erection. Immunohistochemistry of oxytocinergic and serotonergic fibres was performed at the lumbosacral level of the male rat spinal cord, and combined with retrograde tracing from the pelvic nerve or from the ischiocavernosus and bulbospongiosus muscles using wheat germ agglutinin-horseradish peroxidase. Sacral preganglionic neurons retrogradely labelled from the pelvic nerve formed a homogeneous population, predominant at the L6 level. Motoneurons retrogradely labelled from the ischiocavernosus and bulbospongiosus muscles were observed in the medial part of the dorsolateral and in the dorsomedial nuclei. Fibres immunoreactive for oxytocin were mainly distributed in the superficial layers of the dorsal horn, the dorsal gray commissure and the sacral parasympathetic nucleus. Some of these fibres were apposed to retrogradely-labelled sacral preganglionic neurons and at the ultrastructural level, some synapses were evidenced. Fibres immunoreactive for serotonin were largely and densely distributed in the dorsal horn, the dorsal gray commissure, the sacral parasympathetic nucleus and the ventral horn. Some serotonergic fibres occurred in close apposition with retrogradely-labelled sacral preganglionic neurons and motoneurons, and synapses were demonstrated at the ultrastructural level. This study provides morphological support for a role of oxytocin and serotonin on sacral preganglionic neurons innervating pelvic organs and motoneurons innervating the ischiocavernosus and bulbospongiosus muscles.

Stimulation of the medial preoptic area of the hypothalamus in the rat elicits increases in intracavernous pressure

Penile erection can be elicited by various stimuli integrated in the spinal cord and/or higher central nervous structures. The medial preoptic area (MPOA) of the hypothalamus is known to play a key role in the regulation of the male sexual behavior. In anesthetized male rats we performed MPOA stimulation via stereotaxically implanted electrodes or canulae delivering L-glutamate. An erectile response, assessed by an increase of intracavernous pressure (ICP), was recorded during electrical stimulation of the MPOA. Stimulating the posterior region of the MPOA elicited a greater erectile response than stimulation applied to the anterior region. Microinjections of L-glutamate also elicited an ICP increase. Stimulation of MPOA neurons therefore elicits activation of neural pathways controlling penile erection.

Neurophysiology and Pharmacology of Female Genital Sexual Response

Vaginal sexual arousal is a vasocongestive and neuromuscular event controlled by facilitatory parasympathetic and inhibitory sympathetic inputs. Autonomic preganglionic parasympathetic and inhibitory sympathetic fibers to the vagina and clitoris originate in the spinal cord in the sacral parasympathetic nucleus at the sacral level and in the dorsal gray commissure and the intermediolateral cell column at the thoracolumbar level, respectively. Parasympathetic fibers are conveyed by the pelvic nerve, and sympathetic fibers are conveyed by the hypogastric nerve and the paravertebral sympathetic chain. The activity of these spinal nuclei is controlled by descending projections from the brain and sensory afferens (conveyed in the pudendal, hypogastric, pelvic, and vagus nerves) from the genitalia. A key but unresolved issue concerns the neurotransmitters involved in the control of genital sexual arousal. At the peripheral level, acetylcholine plays a minor role in the regulation of vaginal blood flow, however, recent data suggests that it may be involved in the control of vaginal smooth muscle contractions. Vasoactive intestinal peptide and nitric oxide may be responsible for the increase in vaginal blood flow during sexual arousal, whereas noradrenaline is likely inhibitory. Within the central nervous system, serotoninergic projections from the brain to the spinal cord likely inhibit the induction of genital arousal by peripheral infor mations (spinal reflex). Although some neurotransmitters regulating the display of sexual behavior have been identified (for example, dopamine), their involvement in the control of genital sexual arousal has not been invested. Anatomical and electrophysiological data point to a contribution of the paraventricular nucleus of he hypothalamus and the median preoptic area, respectively, as key elements in the control of genital arousal. The recent development of models allowing the assessment of vaginal sexual arousal in anesthetized female rats should assist in deciphering the neurochemical pathways controlling vaginal sexual arousal and the development of suitable pharmacological treatment for female sexual dysfunctions.

5-Hydroxytryptamine2C receptors on spinal neurons controlling penile erection in the rat

The localization of 5-hydroxytryptamine2C receptors in the lumbosacral spinal cord of the rat was investigated using selective antibodies raised against the carboxyl-terminal part of the rat receptor. The distribution of immunoperoxidase labelling at the light microscope level revealed numerous labelled neurons in the gray matter, with a higher intensity in the sacral parasympathetic nucleus, the dorsal gray commissure and particularly the motoneurons of the ventral horn. Confocal microscope analysis showed that immunostaining was mainly intracellular (motoneurons), but could also be associated with the membrane of cell bodies and dendrites. Actually, electron microscope immunogold experiments demonstrated an exclusive staining of the cis-Golgi apparatus. Following pseudo-rabies virus transsynaptic retrograde labelling from the corpus cavernosum, labelled neurons were found in the sacral parasympathetic nucleus and the dorsal gray commissure of the L6-S1 segments. All virus-labelled neurons exhibited 5-hydroxytryptamine2C receptor immunoreactivity. These results indicate that all parasympathetic preganglionic neurons and their related interneurons which contribute to the innervation of cavernosal tissue bear 5-hydroxytryptamine2C receptors. In the sacral parasympathetic nucleus, most neurons which were retrogradely-labelled from the pelvic ganglion with Fast Blue also showed 5-hydroxytryptamine2C receptor immunoreactivity. In the ventral horn, motoneurons retrogradely labelled from the ischiocavernosus muscle and the bulbospongiosus muscle, both of which are involved in erection and ejaculation, were also 5-hydroxytryptamine2C receptor-immunopositive. The supraspinal serotoninergic control of erection at the lumbosacral level therefore appears to be strongly associated with the activation of 5-hydroxytryptamine2C receptors, consistent with the proerectile properties of 5-hydroxytryptamine2C agonists.

Neural control of penile erection in the rat

The role of autonomic and somatic neural pathways involved in the control of penile erectile tissue was investigated in an in vivo rat model. Intracavernous pressure (ICP) changes were recorded during single or combined electrical stimulation of peripheral nerves in anesthetized rats. Stimulation of the pelvic and cavernous nerves elicited similar ICP increases. Ganglionic blockade abolished the response to pelvic nerve stimulation. Stimulation of the hypogastric nerve, the sensory or motor branches of the pudendal nerve, or the paravertebral sympathetic chain at L4-L5 by themselves did not produce any change in ICP. Stimulation of some of these nerves caused changes in ICP when combined with cavernous nerve stimulation. Stimulation of the paravertebral sympathetic chain reduced the ICP increases elicited by cavernous nerve stimulation. A decrease in ICP in response to cavernous nerve stimulation was also elicited by stimulation of the peripheral cut end of the sensory branch of the pudendal nerve or in paralyzed rats, the motor branch of the pudendal nerve. After sectioning the two branches of the pudendal nerve, stimulation of the sympathetic chain still reduced the ICP increase in response to cavernous nerve stimulation. Stimulation of the motor branch of the pudendal nerve during erection elicited by cavernous nerve stimulation was responsible for an additional ICP increase, which reached suprasystolic values. The present study confirms a proerectile role for parasympathetic pathways. Sympathetic fibers conveyed in both branches of the pudendal nerve exert an antierectile role in the rat. We identified an antierectile sympathetic outflow, originating in the caudal sympathetic chain, the anatomical arrangement of which remains unknown. In this model, penile erection appeared to be dependent on the recruitment of sacral parasympathetic outflow. Additional recruitment of efferent somatic fibers present in the motor branch of the pudendal nerve could participate in more rigid erection. This study provides new information about the organization of the pathways through which the rat penis is innervated, and would be of interest to investigators in the field of male sexual function.

Intracavernous pressure during erection in rats: an integrative approach based on telemetric recording

To better understand the similarities and differences in the neural control of penile erection occurring in different contexts, we recorded intracavernous pressure (ICP) in conscious rats using a miniaturized telemetric device. ICP changes during reflexive, noncontact, and apomorphine-induced erections were characterized by a plateau increase surmounted by peaks. Plateaus were also elicited by cavernous nerve stimulation in anesthetized rats, suggesting that the cavernous nerve represents the final common proerectile autonomic pathway in these contexts and that it responds similarly to information originating in the periphery or in supraspinal nuclei. During reflexive, noncontact, and apomorphine-induced erections, activation of spinal autonomic nuclei, considered the spinal generators of erection, would take place first, representing a prerequisite for the occurrence of peaks. Suprasystolic peaks would result from the addition of pudendal motoneuron activity. In contrast, only peaks were recorded during copulation. In this context, the convergence of peripheral and supraspinal information apparently elicits the best temporal arrangement of autonomic and somatic outflows, reflecting a highly organized and integrated spinal activity.

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.

Erectile response to hypothalamic stimulation in rats : role of peripheral nerves

The role of peripheral parasympathetic and sympathetic pathways was explored in erectile responses elicited by hypothalamic medial preoptic area (MPOA) stimulation in adult male anesthetized rats. Under control conditions, MPOA stimulation reliably elicited erectile responses evidenced by an increase of the intracavernous pressure-to-blood pressure ratio. The erectile response was abolished by 1) acute bilateral section of cavernous or pelvic nerves or cauda equina and 2) chronic lesions of pelvic nerves or cauda equina. Acute section of the hypogastric nerve did not significantly decrease the erectile response. The erectile response was significantly depressed after acute or chronic sections of the paravertebral sympathetic chain at the L4-L5 level or chemical sympathectomy with 6-hydroxydopamine. The decrease due to acute sympathetic chain lesion was reversed by bilateral ligation of the external iliac arteries. Accordingly MPOA stimulation elicits erectile responses via 1) activation of the parasympathetic outflow conveyed by the pelvic and cavernous nerves and 2) activation of neural fibers conveyed by the sympathetic pathways. We propose that sympathetic fibers running in the paravertebral sympathetic chain are responsible for vasoconstriction of nonpenile areas to divert blood to the penis, allowing the dramatic increase of penile arterial inflow required for erection.The role of peripheral parasympathetic and sympathetic pathways was explored in erectile responses elicited by hypothalamic medial preoptic area (MPOA) stimulation in adult male anesthetized rats. Under control conditions, MPOA stimulation reliably elicited erectile responses evidenced by an increase of the intracavernous pressure-to-blood pressure ratio. The erectile response was abolished by 1) acute bilateral section of cavernous or pelvic nerves or cauda equina and 2) chronic lesions of pelvic nerves or cauda equina. Acute section of the hypogastric nerve did not significantly decrease the erectile response. The erectile response was significantly depressed after acute or chronic sections of the paravertebral sympathetic chain at the L4-L5 level or chemical sympathectomy with 6-hydroxydopamine. The decrease due to acute sympathetic chain lesion was reversed by bilateral ligation of the external iliac arteries. Accordingly MPOA stimulation elicits erectile responses via 1) activation of the parasympathetic outflow conveyed by the pelvic and cavernous nerves and 2) activation of neural fibers conveyed by the sympathetic pathways. We propose that sympathetic fibers running in the paravertebral sympathetic chain are responsible for vasoconstriction of nonpenile areas to divert blood to the penis, allowing the dramatic increase of penile arterial inflow required for erection.