Central control of penile erection: role of the paraventricular nucleus of the hypothalamus (2005)

Abstract

The paraventricular nucleus of the hypothalamus is an integration centre between the central and peripheral autonomic nervous systems. It is involved in numerous functions from feeding, metabolic balance, blood pressure and heart rate, to erectile function and sexual behaviour.

In particular, a group of oxytocinergic neurons originating in this nucleus and projecting to extra-hypothalamic brain areas (e.g., hippocampus, medulla oblongata and spinal cord) control penile erection in male rats. Activation of these neurons by dopamine and its agonists, excitatory amino acids (N-methyl-D-aspartic acid) or oxytocin itself, or by electrical stimulation leads to penile erection, while their inhibition by gamma-amino-butyric acid (GABA) and its agonists or by opioid peptides and opiate-like drugs inhibits this sexual response.

The activation of these neurons is secondary to the activation of nitric oxide synthase, which produces nitric oxide. Nitric oxide in turn causes, by a mechanism that is as yet unidentified, the release of oxytocin in extra-hypothalamic brain areas. Other compounds recently identified that facilitate penile erection by activating central oxytocinergic neurons are peptide analogues of hexarelin, a growth hormone releasing peptide, pro-VGF-derived peptides, endogenous peptides that may be released by neuronal nerve endings impinging on oxytocinergic cell bodies, SR 141716A, a cannabinoid CB1 receptor antagonist, and, less convincingly, adrenocorticotropin-melanocyte-stimulating hormone (ACTH-MSH)-related peptides.

Paraventricular oxytocinergic neurons and similar mechanisms are also involved in penile erection occurring in physiological contexts, namely noncontact erections that occur in male rats in the presence of an inaccessible receptive female, and during copulation.

These findings show that the paraventricular nucleus of the hypothalamus plays an important role in the control of erectile function and sexual activity. As the male rat is a model of sexual behaviour and penile physiology, which has largely increased in the last years our knowledge of peripheral and central mechanisms controlling erectile function (drugs that induce penile erection in male rats usually do so also in man), the above results may have great significance in terms of a human perspective for the treatment of erectile dysfunction.

Fig. 1. Neuroanatomy of the male genital apparatus: schematic representation. When sexual stimuli reach the central nervous system, they activate neural pathways to date still unknown that are responsible for sexual activity. These travel from the brain, mainly from the hypothalamus and its nuclei (medial preoptic area and paraventricular nucleus), through the medulla oblongata and the spinal cord, to the genital apparatus. This is innervated mainly by pudendal nerves, which originate from the sacral tract of the spinal cord and contain the primary afferent sensory and motor pathways to the penis, and by cavernosal nerves, which contain the primary efferent sympathetic and parasympathetic pathways originating in the pelvic plexuses. These are innervated by hypogastric nerves, which originate in the thoracic-lumbar tract of the spinal cord, by pelvic nerves which originate in the sacral tract of the spinal cord, and by post-gangliar fibers, which originate from the paravertebral sympathetic ganglia chain of the thoracic-lumbar tract of the spinal cord.

Fig. 2. Schematic representation of oxytocinergic neurons, which originate in the paraventricular nucleus of the hypothalamus and project to extra-hypothalamic brain areas and the spinal cord. The activation of these neurons by dopamine, excitatory amino acids, oxytocin itself, hexarelin analogue peptides, and pro-VGF-derived peptides or by the blockade of cannabinoid CB1 receptors leads to penile erection, which can be reduced and/or abolished by the stimulation of opioid and GABAergic receptors. The activation of oxytocinergic neurons is secondary to the activation of nitric oxide-synthase present in these neurons. Indeed endogenous nitric oxide formed by the stimulation of dopamine, excitatory amino acid or oxytocin receptors or exogenous nitric oxide, as that derived from nitric oxide donors given directly into the paraventricular nucleus, activates oxytocinergic neurons by an yet unidentified mechanism. This causes in turn the release of oxytocin in brain areas distant from the paraventricular nucleus inducing penile erection. Mechanisms similar to those described above also operate when penile erection occurs in physiological contexts, namely as when male rats are placed in the presence of an inaccessible receptive female or during copulation.