Neuropeptide Profiles of Mammalian Male Genital Tract: Distribution and Functional Relevance in Reproduction

Humans have a diverse collection of neuropeptides that can influence a multitude of activities. There are now over 100 known neuropeptides and probably many more yet to be identified from the over 1000 predicted peptides encoded in the genome. While diverse, peptides generally share three common characteristics: (1) post-translational processing and release from vesicles, (2) activation of cell-surface receptors over a relatively large distance, and (3) modulation of target cells that are often in the brain and periphery. Within the brain, neuropeptides can modulate the activity of co-released neurotransmitters to either increase or decrease the strength of synaptic signaling. Within the periphery, neuropeptides can function similar to peptide hormones and modulate nearly all bodily functions. Given the clear involvement of the neuropeptide CGRP in migraine and the emerging evidence for other peptides, it seems likely that neuropeptides may help "awaken" the senses and contribute to the heightened sensory state of migraine.

We know neuropeptides now for over 40 years as chemical signals in the brain. The discovery of neuropeptides is founded on groundbreaking research in physiology, endocrinology, and biochemistry during the last century and has been built on three seminal notions: (1) peptide hormones are chemical signals in the endocrine system; (2) neurosecretion of peptides is a general principle in the nervous system; and (3) the nervous system is responsive to peptide signals. These historical lines have contributed to how neuropeptides can be defined today: "Neuropeptides are small proteinaceous substances produced and released by neurons through the regulated secretory route and acting on neural substrates." Thus, neuropeptides are the most diverse class of signaling molecules in the brain engaged in many physiological functions. According to this definition almost 70 genes can be distinguished in the mammalian genome, encoding neuropeptide precursors and a multitude of bioactive neuropeptides. In addition, among cytokines, peptide hormones, and growth factors there are several subfamilies of peptides displaying most of the hallmarks of neuropeptides, for example neural chemokines, cerebellins, neurexophilins, and granins. All classical neuropeptides as well as putative neuropeptides from the latter families are presented as a resource.

Mature male and female Sprague-Dawley rats were used in this study to compare the organization of the pudendal nerve in the two sexes. Experiments included incubating the cut pudendal nerve in diamidino-2-phenylindole HCl (DAPI), fast blue (FB), or horseradish peroxidase (HRP) and injecting individual perineal muscles with these substances. In both sexes, incubation of the pudendal nerve labelled two motoneuron nuclei in the L5-L6 segments of the spinal cord. These nuclei are the dorsomedial (DM) and dorsolateral (DL) cell columns described by Schrøder (J. Comp. Neurol. 192:567-587, 1980). In agreement with previous studies, there were significantly more neurons in both nuclei in the male than in the female and the neurons were larger in the male. In both sexes, the DL and DM nuclei were characterized by a longitudinal dendritic structure. The DM nucleus also had numerous dendritic bundles extending across the midline, linking the DM nuclei bilaterally. Pudendal nerve afferent neurons were located in the L6 and S1 dorsal root ganglia. In the male, the afferent neurons were larger and more numerous. In both sexes, labelled pudendal afferent fibers in the spinal cord were located in the dorsal columns, the medial half of Lissauer's tract, the extreme medial edge of the dorsal horn, both ipsilaterally and contralaterally, and in a large terminal field in the dorsal gray commissure. No labelled afferents were seen in the intermediate or ventral gray. Perineal muscle injections established that there was no difference between males and females in the number of motoneurons innervating the external anal or urethral sphincters. In the female, urethral sphincter motoneurons accounted for almost all the DL motoneurons, and anal sphincter motoneurons accounted for almost all the DM motoneurons. The ischiocavernosus and bulbospongiosus muscles are vestigial in the female rat. In the male, neurons innervating the anal sphincter and bulbospongiosus muscles were intermingled in the DM nucleus. In contrast, in the DL nucleus, the urethral sphincter neurons were located in the lateral portion of the nucleus and the ischiocavernosus neurons were located in the medial portion.