The gastrin-releasing peptide system in the spinal cord mediates masculine sexual function

Abstract

The lumbar spinal segments are of particular interest because they are sexually dimorphic and contain several neuronal circuits that are important in eliciting male sexual responses such as erection and ejaculation. Gastrin-releasing peptide (GRP) is a member of the bombesin-like peptide family first isolated from the porcine stomach. A collection of neurons in the lumbar spinal cord (L3-L4 level) of male rats projects to the lower lumbar spinal cord (L5-L6 level), releasing GRP onto somatic and autonomic centers known to regulate male sexual reflexes. All these target neurons express and localize specific receptors for GRP. This system of GRP neurons is sexually dimorphic, being prominent in male rats but vestigial in females. The system is completely feminine in genetically XY rats with a dysfunctional androgen receptor gene, demonstrating the androgen-dependent nature of the dimorphism. Pharmacological stimulation of GRP receptors in this spinal region remarkably restores sexual reflexes in castrated male rats. Exposure of male rats to a severe traumatic stress decreases the local content and the axonal distribution of GRP in the lumbar spinal cord and results in an attenuation of penile reflexes in vivo. Administration of a specific agonist for GRP receptors restores penile reflexes in the traumatic stress-exposed male rats. This review summarizes findings on this recently identified spinal GRP system, which may be vulnerable to stress, that controls male reproductive function. The identification of a male-specific neuronal system regulating sexual functions offers new avenues for potential therapeutic approaches to masculine reproductive dysfunction.

Impact of androgen deprivation therapy on sexual function

“…It is predominant in male lumbar spinal cord and vestigial in females. 12,13 In another study by Sakamoto et al, 11 the urogenital development of genetically XY rats mutated with a dysfunctional androgen receptor gene was shown to be a female system, showing the androgen-dependent nature of the GRP gene. The same authors showed the pharmacological stimulation of GRP receptors with GRP agonists allowed the restoration of penile reflexes and ejaculation after castration in male rats.…”

Sexually dimorphic nuclei in the spinal cord control male sexual functions

“…Using immunohistochemistry for gastrin-releasing peptide (GRP) in rats, we newly identified a collection of neurons containing GRP in the lumbar spinal region (L3–L4 level), showing a clear male-dominant sexual dimorphism (Sakamoto et al, 2008; Sakamoto, 2011) (Figure 2). These GRP-expressing neurons send axons onto the more caudal segments of the lumbosacral spinal cord (L5–L6 and S1 levels), including the autonomic sacral parasympathetic nucleus (SPN) as well as the somatic spinal nucleus of the bulbocavernosus (SNB) (Sakamoto et al, 2008).…”

“…The identification of this male-specific neural system using a specific neuropeptide, GRP, that controls sexual function offers new approaches for the development of pharmacological treatments to relief the male reproductive dysfunction (Sakamoto, 2011). In addition to the parasympathetic nucleus, LSt neurons in the spinal cord project to the sympathetic neurons of the intermediolateral column in the thoracic spinal cord, which is crucial for the emission phase of ejaculation (Coolen, 2005; Kozyrev et al, 2012).…”

“…Therefore, these 3-D results taken together suggested that GRP-containing afferents to SNB motoneurons may control penile reflexes during sexual behavior through the identified GRP-SNB synapses (Sakamoto et al, 2010). Nevertheless, the functional synchronization of these two neural systems in the lower spinal cord is required for normal penile reflexes (Sakamoto, 2011). Using HVEM, we further demonstrated that the terminals of GRP neurons may form 3-D multiple synapses with the dendrites of SPN neurons revealed by a double immunohistochemical study (Oti et al, 2012).…”

Ultrahigh Voltage Electron Microscopy Links Neuroanatomy and Neuroscience/Neuroendocrinology

“…In the central nervous system, a population of synaptic inputs from a brain nucleus can influence axosomatic synapses whereas the structural analysis of multiple major synaptic inputs into the dendrites located outside the nucleus is difficult to perform methodologically. However, using UHVEM we overcame these difficulties and described a powerful methodology to study the chemical neuroanatomy of 3D ultrastructures [8, 9]. Here, 3D analysis of neuroanatomy at the ultrastructural level using UHVEM is summarized.…”