Anatomical Science International

, Volume 86, Issue 1, pp 19–29 | Cite as

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

  • Hirotaka SakamotoEmail author
Review Article


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.


Gastrin-releasing peptide Lumbar spinal cord Androgens Male sexual function 



I thank Dr. Damian G. Zuloaga (University of Arizona College of Medicine-Phoenix, AZ, USA) for valuable discussions, reading the manuscript and collaboration. I am grateful to Drs. Mitsuhiro Kawata, Ken-Ichi Matsuda, Keiko Takanami, Hisayuki Hongu, Nobuko Nishiura, Etsuko Wada, Keiji Wada, Tatsuo Arii, Tatsuya Sakamoto, Cynthia L. Jordan and S. Marc Breedlove for their valuable discussions and collaborations. This work was supported by Grants-in-Aid Scientific Research [Encouragement of Young Scientists (A): no. 21680031, (B): no. 19700319] from the Ministry of Education, Science, Sports, Culture and Technology, Japan; by Grants-in-Aid for Young Scientists (Start-up) from Okayama University, Japan; by The Naito Memorial Grant for Natural Science Researches, Japan; by The Uehara Memorial Foundation, Japan; by The Inamori Foundation, Japan; by Narishige Neuroscience Research Foundation, Japan; and by Co-operative Study by High-voltage Electron Microscopy (H-1250M) from the National Institute for Physiological Sciences, Okazaki, Japan. All experimental procedures for the author’s research project cited in the present review have been authorized by the Committee for Animal Research, Kyoto Prefectural University of Medicine and Okayama University, Japan and/or the Institutional Animal Care and Use Committee of Michigan State University, MI, USA. The author is a recipient of the Incitement Award of the Japanese Association of Anatomists in the fiscal year 2009, and a part of the present work was presented at the 115th annual meeting in Morioka, Iwate, Japan, 28–30 March 2010.


  1. Anastasi A, Erspamer V, Bucci M (1971) Isolation and structure of bombesin and alytesin, 2 analogous active peptides from the skin of the European amphibians Bombina and Alytes. Experientia 27:166–167CrossRefPubMedGoogle Scholar
  2. Bardin CW, Bullock L, Blackburn WR, Sherins RJ, Vanha-Perttula T (1971) Testosterone metabolism in the androgen-insensitive rat: a model for testicular feminization. Birth Defects Orig Artic Ser 7:185–192PubMedGoogle Scholar
  3. Battey J, Wada E (1991) Two distinct receptor subtypes for mammalian bombesin-like peptides. Trends Neurosci 14:524–528CrossRefPubMedGoogle Scholar
  4. Battey JF, Way JM, Corjay MH et al (1991) Molecular cloning of the bombesin/gastrin-releasing peptide receptor from Swiss 3T3 cells. Proc Natl Acad Sci USA 88:395–399CrossRefPubMedGoogle Scholar
  5. Bauer M, Priebe S, Graf KJ, Kurten I, Baumgartner A (1994) Psychological and endocrine abnormalities in refugees from East Germany: part II. Serum levels of cortisol, prolactin, luteinizing hormone, follicle stimulating hormone, and testosterone. Psychiatry Res 51:75–85CrossRefPubMedGoogle Scholar
  6. Breedlove SM (1985) Hormonal control of the anatomical specificity of motoneuron-to-muscle innervation in rats. Science 227:1357–1359CrossRefPubMedGoogle Scholar
  7. Breedlove SM, Arnold AP (1980) Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal cord. Science 210:564–566CrossRefPubMedGoogle Scholar
  8. Breedlove SM, Arnold AP (1981) Sexually dimorphic motor nucleus in the rat lumbar spinal cord: response to adult hormone manipulation, absence in androgen-insensitive rats. Brain Res 225:297–307CrossRefPubMedGoogle Scholar
  9. Breedlove SM, Arnold AP (1983a) Hormonal control of a developing neuromuscular system. I. Complete demasculinization of the male rat spinal nucleus of the bulbocavernosus using the anti-androgen flutamide. J Neurosci 3:417–423PubMedGoogle Scholar
  10. Breedlove SM, Arnold AP (1983b) Hormonal control of a developing neuromuscular system. II. Sensitive periods for the androgen-induced masculinization of the rat spinal nucleus of the bulbocavernosus. J Neurosci 3:424–432PubMedGoogle Scholar
  11. Coolen LM (2005) Neural control of ejaculation. J Comp Neurol 493:39–45CrossRefPubMedGoogle Scholar
  12. Cosgrove DJ, Gordon Z, Bernie JE et al (2002) Sexual dysfunction in combat veterans with post-traumatic stress disorder. Urology 60:881–884CrossRefPubMedGoogle Scholar
  13. Cui H, Sakamoto H, Higashi S, Kawata M (2008) Effects of single-prolonged stress on neurons and their afferent inputs in the amygdala. Neuroscience 152:703–712CrossRefPubMedGoogle Scholar
  14. Fathi Z, Corjay MH, Shapira H et al (1993) BRS-3: a novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J Biol Chem 268:5979–5984PubMedGoogle Scholar
  15. Forger NG (2009) The organizational hypothesis and final common pathways: sexual differentiation of the spinal cord and peripheral nervous system. Horm Behav 55:605–610CrossRefPubMedGoogle Scholar
  16. Forger NG, Breedlove SM (1986) Sexual dimorphism in human and canine spinal cord: role of early androgen. Proc Natl Acad Sci USA 83:7527–7531CrossRefPubMedGoogle Scholar
  17. Forger NG, Fishman RB, Breedlove SM (1992) Differential effects of testosterone metabolites upon the size of sexually dimorphic motoneurons in adulthood. Horm Behav 26:204–213CrossRefPubMedGoogle Scholar
  18. Goldstein LA, Kurz EM, Sengelaub DR (1990) Androgen regulation of dendritic growth and retraction in the development of a sexually dimorphic spinal nucleus. J Neurosci 10:935–946PubMedGoogle Scholar
  19. Hart BL (1973) Effects of testosterone propionate and dihydrotestosterone on penile morphology and sexual reflexes of spinal male rats. Horm Behav 4:239–246CrossRefGoogle Scholar
  20. Hart BL (1979) Activation of sexual reflexes of male rats by dihydrotestosterone but not estrogen. Physiol Behav 23:107–109CrossRefPubMedGoogle Scholar
  21. Hart BL, Haugen CM (1968) Activation of sexual reflexes in male rats by spinal implantation of testosterone. Physiol Behav 3:735–738CrossRefGoogle Scholar
  22. Hull EM, Dominguez JM (2007) Sexual behavior in male rodents. Horm Behav 52:45–55CrossRefPubMedGoogle Scholar
  23. Ju G, Melander T, Ceccatelli S, Hokfelt T, Frey P (1987) Immunohistochemical evidence for a spinothalamic pathway co-containing cholecystokinin- and galanin-like immunoreactivities in the rat. Neuroscience 20:439–456CrossRefPubMedGoogle Scholar
  24. Kaplan HS (1988) Anxiety and sexual dysfunction. J Clin Psychiatry 49(Suppl):21–25PubMedGoogle Scholar
  25. Kaplan HS (1989) Post-traumatic stress syndrome and sexual dysfunction. J Sex Marital Ther 15:74–77PubMedGoogle Scholar
  26. Karatsoreos IN, Romeo RD, McEwen BS, Silver R (2006) Diurnal regulation of the gastrin-releasing peptide receptor in the mouse circadian clock. Eur J Neurosci 23:1047–1053CrossRefPubMedGoogle Scholar
  27. Khan S, Liberzon I (2004) Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD. Psychopharmacology (Berl) 172:225–229CrossRefGoogle Scholar
  28. Kohda K, Harada K, Kato K et al (2007) Glucocorticoid receptor activation is involved in producing abnormal phenotypes of single-prolonged stress rats: a putative post-traumatic stress disorder model. Neuroscience 148:22–33CrossRefPubMedGoogle Scholar
  29. Kojima M, Sano Y (1984) Sexual differences in the topographical distribution of serotonergic fibers in the anterior column of rat lumbar spinal cord. Anat Embryol (Berl) 170:117–121CrossRefGoogle Scholar
  30. Kojima M, Takeuchi Y, Goto M, Sano Y (1983) Immunohistochemical study on the localization of serotonin fibers and terminals in the spinal cord of the monkey (Macaca fuscata). Cell Tissue Res 229:23–36CrossRefPubMedGoogle Scholar
  31. Kojima M, Matsuura T, Kimura H, Nojyo Y, Sano Y (1984) Fluorescence histochemical study on the noradrenergic control to the anterior column of the spinal lumbosacral segments of the rat and dog, with special reference to motoneurons innervating the perineal striated muscles (Onuf’s nucleus). Histochemistry 81:237–241CrossRefPubMedGoogle Scholar
  32. Kreuz LE, Rose RM, Jennings JR (1972) Suppression of plasma testosterone levels and psychological stress. A longitudinal study of young men in Officer Candidate School. Arch Gen Psychiatry 26:479–482PubMedGoogle Scholar
  33. Kroog GS, Jensen RT, Battey JF (1995) Mammalian bombesin receptors. Med Res Rev 15:389–417CrossRefPubMedGoogle Scholar
  34. Kurz EM, Sengelaub DR, Arnold AP (1986) Androgens regulate the dendritic length of mammalian motoneurons in adulthood. Science 232:395–398CrossRefPubMedGoogle Scholar
  35. Ladenheim EE, Taylor JE, Coy DH, Moore KA, Moran TH (1996) Hindbrain GRP receptor blockade antagonizes feeding suppression by peripherally administered GRP. Am J Physiol 271:R180–R184PubMedGoogle Scholar
  36. Ladenheim EE, Behles RR, Bi S, Moran TH (2009) Gastrin-releasing peptide messenger ribonucleic acid expression in the hypothalamic paraventricular nucleus is altered by melanocortin receptor stimulation and food deprivation. Endocrinology 150:672–678CrossRefPubMedGoogle Scholar
  37. Letourneau EJ, Schewe PA, Frueh BC (1997) Preliminary evaluation of sexual problems in combat veterans with PTSD. J Trauma Stress 10:125–132PubMedGoogle Scholar
  38. Liberzon I, Krstov M, Young EA (1997) Stress–restress: effects on ACTH and fast feedback. Psychoneuroendocrinology 22:443–453CrossRefPubMedGoogle Scholar
  39. Liberzon I, Lopez JF, Flagel SB, Vazquez DM, Young EA (1999) Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder. J Neuroendocrinol 11:11–17CrossRefPubMedGoogle Scholar
  40. Martinez V, Tache Y (2000) Bombesin and the brain–gut axis. Peptides 21:1617–1625CrossRefPubMedGoogle Scholar
  41. Mason JW, Giller EL, Kosten TR (1988) Serum testosterone differences between patients with schizophrenia and those with affective disorder. Biol Psychiatry 23:357–366CrossRefPubMedGoogle Scholar
  42. Matsumoto A (2001) Androgen stimulates neuronal plasticity in the perineal motoneurons of aged male rats. J Comp Neurol 430:389–395CrossRefPubMedGoogle Scholar
  43. Matsumoto A, Micevych PE, Arnold AP (1988) Androgen regulates synaptic input to motoneurons of the adult rat spinal cord. J Neurosci 8:4168–4176PubMedGoogle Scholar
  44. McDonald TJ, Jornvall H, Nilsson G et al (1979) Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun 90:227–233CrossRefPubMedGoogle Scholar
  45. Merali Z, Bedard T, Andrews N et al (2006) Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity. J Neurosci 26:10387–10396CrossRefPubMedGoogle Scholar
  46. Meston CM, Frohlich PF (2000) The neurobiology of sexual function. Arch Gen Psychiatry 57:1012–1030CrossRefPubMedGoogle Scholar
  47. Minamino N, Kangawa K, Matsuo H (1983) Neuromedin B: a novel bombesin-like peptide identified in porcine spinal cord. Biochem Biophys Res Commun 114:541–548CrossRefPubMedGoogle Scholar
  48. Morris JA, Jordan CL, Breedlove SM (2004) Sexual differentiation of the vertebrate nervous system. Nat Neurosci 7:1034–1039CrossRefPubMedGoogle Scholar
  49. Mulchahey JJ, Ekhator NN, Zhang H, Kasckow JW, Baker DG, Geracioti TD Jr (2001) Cerebrospinal fluid and plasma testosterone levels in post-traumatic stress disorder and tobacco dependence. Psychoneuroendocrinology 26:273–285CrossRefPubMedGoogle Scholar
  50. Nakagawa S (1980) Onuf’s nucleus of the sacral cord in a South American monkey (Saimiri): its location and bilateral cortical input from area 4. Brain Res 191:337–344CrossRefPubMedGoogle Scholar
  51. Newton BW (1992) A sexually dimorphic population of galanin-like neurons in the rat lumbar spinal cord: functional implications. Neurosci Lett 137:119–122CrossRefPubMedGoogle Scholar
  52. Nicholas AP, Zhang X, Hokfelt T (1999) An immunohistochemical investigation of the opioid cell column in lamina X of the male rat lumbosacral spinal cord. Neurosci Lett 270:9–12CrossRefPubMedGoogle Scholar
  53. Okamura H, Ibata Y (1994) GRP immunoreactivity shows a day–night difference in the suprachiasmatic nuclear soma and efferent fibers: comparison to VIP immunoreactivity. Neurosci Lett 181:165–168CrossRefPubMedGoogle Scholar
  54. Onufrowicz B (1899) Notes on the arrangement and function of the cell groups in the sacral region of the spinal cord. J Nerv Mental Dis 26:498–504CrossRefGoogle Scholar
  55. Panula P, Nieminen O, Falkenberg M, Auvinen S (1988) Localization and development of bombesin/GRP-like immunoreactivity in the rat central nervous system. Ann N Y Acad Sci 547:54–69CrossRefPubMedGoogle Scholar
  56. Phan DC, Newton BW (1999) Cholecystokinin-8-like immunoreactivity is sexually dimorphic in a midline population of rat lumbar neurons. Neurosci Lett 276:165–168CrossRefPubMedGoogle Scholar
  57. Pitman RK (1997) Overview of biological themes in PTSD. Ann N Y Acad Sci 821:1–9CrossRefPubMedGoogle Scholar
  58. Quigley CA, De Bellis A, Marschke KB, el-Awady MK, Wilson EM, French FS (1995) Androgen receptor defects: historical, clinical, and molecular perspectives. Endocr Rev 16:271–321PubMedGoogle Scholar
  59. Rajfer J (2000) Relationship between testosterone and erectile dysfunction. Rev Urol 2:122–128PubMedGoogle Scholar
  60. Retana-Marquez S, Bonilla-Jaime H, Vazquez-Palacios G, Martinez-Garcia R, Velazquez-Moctezuma J (2003) Changes in masculine sexual behavior, corticosterone and testosterone in response to acute and chronic stress in male rats. Horm Behav 44:327–337CrossRefPubMedGoogle Scholar
  61. Roesler R, Lessa D, Venturella R et al (2004) Bombesin/gastrin-releasing peptide receptors in the basolateral amygdala regulate memory consolidation. Eur J Neurosci 19:1041–1045CrossRefPubMedGoogle Scholar
  62. Rosen RC, Sachs BD (2000) Central mechanisms in the control of penile erection: current theory and research. Neurosci Biobehav Rev 24:503–505CrossRefPubMedGoogle Scholar
  63. Sachs BD (1982) Role of striated penile muscles in penile reflexes, copulation, and induction of pregnancy in the rat. J Reprod Fertil 66:433–443CrossRefPubMedGoogle Scholar
  64. Sakamoto H (2010) The neurobiology of psychogenic erectile dysfunction in the spinal cord. J Androl. doi: 10.2164/jandrol.110.010041
  65. Sakamoto H, Kawata M (2006) Distribution of gastrin releasing peptide in the rat lumbar spinal cord is sexually dimorphic and regulated by androgen. Front Neuroendocrinol 27:46CrossRefGoogle Scholar
  66. Sakamoto H, Kawata M (2009) Gastrin-releasing peptide system in the spinal cord controls male sexual behaviour. J Neuroendocrinol 21:432–435CrossRefPubMedGoogle Scholar
  67. Sakamoto H, Matsuda K-I, Zuloaga DG et al (2008) Sexually dimorphic gastrin releasing peptide system in the spinal cord controls male reproductive functions. Nat Neurosci 11:634–636CrossRefPubMedGoogle Scholar
  68. Sakamoto H, Matsuda K-I, Zuloaga DG et al (2009a) Stress affects a gastrin-releasing peptide system in the spinal cord that mediates sexual function: implications for psychogenic erectile dysfunction. PLoS ONE 4:e4276CrossRefPubMedGoogle Scholar
  69. Sakamoto H, Takanami K, Zuloaga DG et al (2009b) Androgen regulates the sexually dimorphic gastrin-releasing peptide system in the lumbar spinal cord that mediates male sexual function. Endocrinology 150:3672–3679CrossRefPubMedGoogle Scholar
  70. Sakamoto H, Arii T, Kawata M (2010) High-voltage electron microscopy reveals direct synaptic inputs from a spinal gastrin-releasing peptide system to neurons of the spinal nucleus of bulbocavernosus. Endocrinology 151:417–421CrossRefPubMedGoogle Scholar
  71. Sato M, Mizuno N, Konishi A (1978) Localization of motoneurons innervating perineal muscles: a HRP study in cat. Brain Res 140:149–154CrossRefPubMedGoogle Scholar
  72. Seidman SN, Roose SP (2001) Sexual dysfunction and depression. Curr Psychiatry Rep 3:202–208CrossRefPubMedGoogle Scholar
  73. Sengelaub DR, Forger NG (2008) The spinal nucleus of the bulbocavernosus: firsts in androgen-dependent neural sex differences. Horm Behav 53:596–612CrossRefPubMedGoogle Scholar
  74. Shinohara K, Tominaga K, Isobe Y, Inouye ST (1993) Photic regulation of peptides located in the ventrolateral subdivision of the suprachiasmatic nucleus of the rat: daily variations of vasoactive intestinal polypeptide, gastrin-releasing peptide, and neuropeptide Y. J Neurosci 13:793–800PubMedGoogle Scholar
  75. Shumyatsky GP, Tsvetkov E, Malleret G et al (2002) Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111:905–918CrossRefPubMedGoogle Scholar
  76. Sun YG, Chen ZF (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448:700–703CrossRefPubMedGoogle Scholar
  77. Sun XQ, Xu C, Leclerc P, Benoit G, Giuliano F, Droupy S (2009a) Spinal neurons involved in the control of the seminal vesicles: a transsynaptic labeling study using pseudorabies virus in rats. Neuroscience 158:786–797CrossRefPubMedGoogle Scholar
  78. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF (2009b) Cellular basis of itch sensation. Science 325:1531–1534CrossRefPubMedGoogle Scholar
  79. Swain MG (2008) Gastrin-releasing peptide and pruritus: more than just scratching the surface. J Hepatol 48:681–683CrossRefPubMedGoogle Scholar
  80. Takahashi T, Morinobu S, Iwamoto Y, Yamawaki S (2006) Effect of paroxetine on enhanced contextual fear induced by single prolonged stress in rats. Psychopharmacology (Berl) 189:165–173CrossRefGoogle Scholar
  81. Truitt WA, Coolen LM (2002) Identification of a potential ejaculation generator in the spinal cord. Science 297:1566–1569CrossRefPubMedGoogle Scholar
  82. Truitt WA, Shipley MT, Veening JG, Coolen LM (2003) Activation of a subset of lumbar spinothalamic neurons after copulatory behavior in male but not female rats. J Neurosci 23:325–331PubMedGoogle Scholar
  83. Vizzard MA, Erdman SL, de Groat WC (1995) Increased expression of neuronal nitric oxide synthase (NOS) in visceral neurons after nerve injury. J Neurosci 15:4033–4045PubMedGoogle Scholar
  84. Wada E, Way J, Shapira H et al (1991) cDNA cloning, characterization and brain region-specific expression of neuromedin B-preferring bombesin receptor. Neuron 6:421–430CrossRefPubMedGoogle Scholar
  85. Xu C, Yaici ED, Conrath M et al (2005) Galanin and neurokinin-1 receptor immunoreactive [corrected] spinal neurons controlling the prostate and the bulbospongiosus muscle identified by transsynaptic labeling in the rat. Neuroscience 134:1325–1341CrossRefPubMedGoogle Scholar
  86. Xu C, Giuliano F, Yaici ED et al (2006) Identification of lumbar spinal neurons controlling simultaneously the prostate and the bulbospongiosus muscles in the rat. Neuroscience 138:561–573CrossRefPubMedGoogle Scholar
  87. Yamada K, Wada E, Wada K (2000) Bombesin-like peptides: studies on food intake and social behaviour with receptor knock-out mice. Ann Med 32:519–529CrossRefPubMedGoogle Scholar
  88. Yang LY, Verhovshek T, Sengelaub DR (2004) Brain-derived neurotrophic factor and androgen interact in the maintenance of dendritic morphology in a sexually dimorphic rat spinal nucleus. Endocrinology 145:161–168CrossRefPubMedGoogle Scholar
  89. Yarbrough WG, Quarmby VE, Simental JA et al (1990) A single base mutation in the androgen receptor gene causes androgen insensitivity in the testicular feminized rat. J Biol Chem 265:8893–8900PubMedGoogle Scholar
  90. Yehuda R (2002) Post-traumatic stress disorder. N Engl J Med 346:108–114CrossRefPubMedGoogle Scholar
  91. Yoshii T, Sakamoto H, Kawasaki M et al (2008) The single-prolonged stress paradigm alters both the morphology and stress response of magnocellular vasopressin neurons. Neuroscience 156:466–474CrossRefPubMedGoogle Scholar
  92. Zuloaga DG, Puts DA, Jordan CL, Breedlove SM (2008) The role of androgen receptors in the masculinization of brain and behavior: what we’ve learned from the testicular feminization mutation. Horm Behav 53:613–626CrossRefPubMedGoogle Scholar

Copyright information

© Japanese Association of Anatomists 2010

Authors and Affiliations

  1. 1.Ushimado Marine Laboratory, Graduate School of Natural Science and TechnologyOkayama UniversitySetouchiJapan
  2. 2.Department of Anatomy and NeurobiologyKyoto Prefectural University of MedicineKyotoJapan

Personalised recommendations