Abstract
It is an established fact that orexin plays an important role in regulating the reproductive axis and the secretions of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH). However, its precise cellular and molecular mechanisms are not fully recognized. Accordingly, the aim of the present study is to find out whether the central injection of orexin A (OXA) and its antagonists, SB-334867 (as orexin receptor antagonist 1; OX1RA) and JNJ-10397049 (as orexin receptor antagonist 2; OX2RA), either alone or in combination, can leave any impact on the reproductive axis (either hormonal or behavioral) in the male Wistar rats. Furthermore, in order to see whether OXA signals can be relayed through the pathway of kisspeptin/neurokinin B/dynorphin (known as KNDy neurons, a neural network which works upstream of GnRH neurons) or not, the relative gene expression of these neuropeptides were measured. Overall, the data from radioimmunoassay revealed that OXA significantly decreases the mean serum level of LH and testosterone and, in a similar vein, its antagonists neutralize this impact. Moreover, data from real-time quantitative PCR indicated that OXA has significantly reduced the hypothalamic expression of Gnrh. In this line, the gene expressions of Kisspeptin and Neurokinin b decreased. However, OXA antagonists neutralize this impact. Also, the expression of Dynorphin gene was upregulated by the following application of the OXA. The results of this study are related to the impact of orexin on the reproductive axis. It is recommended that KNDy neurons as the interneural pathway relay the information of orexin to the GnRH neurons.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Agmo, A., Paredes, R., & Fernandez, H. (1987). Differential effects of GABA transaminase inhibitors on sexual behavior, locomotor activity, and motor execution in the male rat. Pharmacology Biochemistry and Behavior, 28(1), 47–52.
Amstalden, M., Coolen, L. M., Hemmerle, A. M., Billings, H. J., Connors, J. M., Goodman, R. L., et al. (2010). Neurokinin 3 receptor immunoreactivity in the septal region, preoptic area and hypothalamus of the female sheep: Colocalisation in neurokinin B cells of the arcuate nucleus but not in gonadotrophin-releasing hormone neurones. Journal of Neuroendocrinology, 22(1), 1–12. https://doi.org/10.1111/j.1365-2826.2009.01930.x.
Anderson, R. I., Moorman, D. E., & Becker, H. C. (2018). Contribution of dynorphin and orexin neuropeptide systems to the motivational effects of alcohol. Handbook of Experimental Pharmacology. https://doi.org/10.1007/164_2018_100.
Bai, Y. J., Li, Y. H., Zheng, X. G., Han, J., Yang, X. Y., & Sui, N. (2009). Orexin A attenuates unconditioned sexual motivation in male rats. Pharmacology Biochemistry and Behavior, 91(4), 581–589. https://doi.org/10.1016/j.pbb.2008.09.018.
Baimel, C., Lau, B. K., Qiao, M., & Borgland, S. L. (2017). Projection-target-defined effects of orexin and dynorphin on VTA dopamine neurons. Cell Report, 18(6), 1346–1355. https://doi.org/10.1016/j.celrep.2017.01.030.
Barb, C. R., & Matteri, R. L. (2005). Orexin-B modulates luteinizing hormone and growth hormone secretion from porcine pituitary cells in culture. Domestic Animal Endocrinology, 28(3), 331–337. https://doi.org/10.1016/j.domaniend.2004.09.005.
Campbell, R. E., Grove, K. L., & Smith, M. S. (2003). Gonadotropin-releasing hormone neurons coexpress orexin 1 receptor immunoreactivity and receive direct contacts by orexin fibers. Endocrinology, 144(4), 1542–1548. https://doi.org/10.1210/en.2002-220958.
Cataldi, N. I., Lux-Lantos, V. A., & Libertun, C. (2012). Effects of orexins A and B on expression of orexin receptors and progesterone release in luteal and granulosa ovarian cells. Regulatory Peptides, 178(1–3), 56–63. https://doi.org/10.1016/j.regpep.2012.06.008.
Czerwinska, J., Chojnowska, K., Kaminski, T., Bogacka, I., Smolinska, N., & Kaminska, B. (2017). Orexin receptor expression in the hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes of free-living European beavers (Castor fiber L.) in different periods of the reproductive cycle. General and Comparative Endocrinology, 240, 103–113. https://doi.org/10.1016/j.ygcen.2016.09.013.
Furuta, M., Funabashi, T., & Kimura, F. (2002). Suppressive action of orexin A on pulsatile luteinizing hormone secretion is potentiated by a low dose of estrogen in ovariectomized rats. Neuroendocrinology, 75(3), 151–157. https://doi.org/10.1159/000048232.
Gaskins, G. T., & Moenter, S. M. (2012). Orexin a suppresses gonadotropin-releasing hormone (GnRH) neuron activity in the mouse. Endocrinology, 153(8), 3850–3860. https://doi.org/10.1210/en.2012-1300.
Goodman, R. L., Coolen, L. M., & Lehman, M. N. (2014). A role for neurokinin B in pulsatile GnRH secretion in the ewe. Neuroendocrinology, 99(1), 18–32. https://doi.org/10.1159/000355285.
Goodman, R. L., Lehman, M. N., Smith, J. T., Coolen, L. M., de Oliveira, C. V., Jafarzadehshirazi, M. R., et al. (2007). Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology, 148(12), 5752–5760. https://doi.org/10.1210/en.2007-0961.
Gulia, K. K., Mallick, H. N., & Kumar, V. M. (2003). Orexin A (hypocretin-1) application at the medial preoptic area potentiates male sexual behavior in rats. Neuroscience, 116(4), 921–923.
Herbison, A. E., de Tassigny, X., Doran, J., & Colledge, W. H. (2010). Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology, 151(1), 312–321. https://doi.org/10.1210/en.2009-0552.
Hunt, N. J., Waters, K. A., & Machaalani, R. (2017). Promotion of the unfolding protein response in orexin/dynorphin neurons in sudden infant death syndrome (SIDS): Elevated pPERK and ATF4 expression. Molecular Neurobiology, 54(9), 7171–7185. https://doi.org/10.1007/s12035-016-0234-3.
Inutsuka, A., & Yamanaka, A. (2013). The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions. Frontiers in Endocrinology (Lausanne), 4, 18. https://doi.org/10.3389/fendo.2013.00018.
Irahara, M., Tamura, T., Matuzaki, T., Saito, S., Yasui, T., Yamano, S., et al. (2001). Orexin-A suppresses the pulsatile secretion of luteinizing hormone via beta-endorphin. Biochemical and Biophysical Research Communications, 281(1), 232–236. https://doi.org/10.1006/bbrc.2001.4328.
Iwasa, T., Matsuzaki, T., Kiyokawa, M., Shimizu, F., Minakuchi, M., Kuwahara, A., et al. (2007). The type 2 corticotrophin-releasing hormone receptor mediates orexin A-induced luteinising hormone suppression in ovariectomised rats. Journal of Neuroendocrinology, 19(9), 732–738. https://doi.org/10.1111/j.1365-2826.2007.01583.x.
Kohsaka, A., Watanobe, H., Kakizaki, Y., Suda, T., & Schioth, H. B. (2001). A significant participation of orexin-A, a potent orexigenic peptide, in the preovulatory luteinizing hormone and prolactin surges in the rat. Brain Research, 898(1), 166–170.
Lehman, M. N., Coolen, L. M., & Goodman, R. L. (2010). Minireview: Kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: A central node in the control of gonadotropin-releasing hormone secretion. Endocrinology, 151(8), 3479–3489. https://doi.org/10.1210/en.2010-0022.
Lehman, M. N., Hileman, S. M., & Goodman, R. L. (2013). Neuroanatomy of the kisspeptin signaling system in mammals: Comparative and developmental aspects. Advances in Experimental Medicine and Biology, 784, 27–62. https://doi.org/10.1007/978-1-4614-6199-9_3.
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 25(4), 402–408. https://doi.org/10.1006/meth.2001.1262.
Mikkelsen, J. D., & Simonneaux, V. (2009). The neuroanatomy of the kisspeptin system in the mammalian brain. Peptides, 30(1), 26–33. https://doi.org/10.1016/j.peptides.2008.09.004.
Muschamp, J. W., Dominguez, J. M., Sato, S. M., Shen, R. Y., & Hull, E. M. (2007). A role for hypocretin (orexin) in male sexual behavior. Journal of Neuroscience, 27(11), 2837–2845. https://doi.org/10.1523/jneurosci.4121-06.2007.
Navarro, V. M., Castellano, J. M., McConkey, S. M., Pineda, R., Ruiz-Pino, F., Pinilla, L., et al. (2011). Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. American Journal of Physiology-Endocrinology and Metabolism, 300(1), E202–E210. https://doi.org/10.1152/ajpendo.00517.2010.
Nurmio, M., Tena-Sempere, M., & Toppari, J. (2010). Orexins and the regulation of the hypothalamic–pituitary–testicular axis. Acta Physiologica (Oxf), 198(3), 349–354. https://doi.org/10.1111/j.1748-1716.2009.02006.x.
Paxinos, G., & Watson, C. (2014). Paxinos and Watson’s the rat brain in stereotaxic coordinates (7th edn.). London: Academic Press.
Pillon, D., Caraty, A., Fabre-Nys, C., & Bruneau, G. (2003). Short-term effect of oestradiol on neurokinin B mRNA expression in the infundibular nucleus of ewes. Journal of Neuroendocrinology, 15(8), 749–753.
Pinilla, L., Aguilar, E., Dieguez, C., Millar, R. P., & Tena-Sempere, M. (2012). Kisspeptins and reproduction: Physiological roles and regulatory mechanisms. Physiological Reviews, 92(3), 1235–1316. https://doi.org/10.1152/physrev.00037.2010.
Pu, S., Jain, M. R., Kalra, P. S., & Kalra, S. P. (1998). Orexins, a novel family of hypothalamic neuropeptides, modulate pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner. Regulatory Peptides, 78(1–3), 133–136.
Rance, N. E., Krajewski, S. J., Smith, M. A., Cholanian, M., & Dacks, P. A. (2010). Neurokinin B and the hypothalamic regulation of reproduction. Brain Research, 1364, 116–128. https://doi.org/10.1016/j.brainres.2010.08.059.
Russell, S. H., Small, C. J., Dakin, C. L., Abbott, C. R., Morgan, D. G., Ghatei, M. A., et al. (2001). The central effects of orexin-A in the hypothalamic–pituitary–adrenal axis in vivo and in vitro in male rats. Journal of Neuroendocrinology, 13(6), 561–566.
Sakurai, T. (2014). The role of orexin in motivated behaviours. Nature Reviews Neuroscience, 15(11), 719–731. https://doi.org/10.1038/nrn3837.
Sasson, R., Dearth, R. K., White, R. S., Chappell, P. E., & Mellon, P. L. (2006). Orexin A induces GnRH gene expression and secretion from GT1-7 hypothalamic GnRH neurons. Neuroendocrinology, 84(6), 353–363. https://doi.org/10.1159/000098333.
Seminara, S. B., Messager, S., Chatzidaki, E. E., Thresher, R. R., Acierno, J. S. Jr., Shagoury, J. K., et al. (2003). The GPR54 gene as a regulator of puberty. New England Journal of Medicine, 349(17), 1614–1627. https://doi.org/10.1056/NEJMoa035322.
Small, C. J., Goubillon, M. L., Murray, J. F., Siddiqui, A., Grimshaw, S. E., Young, H., et al. (2003). Central orexin A has site-specific effects on luteinizing hormone release in female rats. Endocrinology, 144(7), 3225–3236. https://doi.org/10.1210/en.2002-0041.
Su, J., Lei, Z., Zhang, W., Ning, H., & Ping, J. (2008). Distribution of orexin B and its relationship with GnRH in the pig hypothalamus. Research in Veterinary Science, 85(2), 315–323. https://doi.org/10.1016/j.rvsc.2007.12.007.
Tamura, T., Irahara, M., Tezuka, M., Kiyokawa, M., & Aono, T. (1999). Orexins, orexigenic hypothalamic neuropeptides, suppress the pulsatile secretion of luteinizing hormone in ovariectomized female rats. Biochemical and Biophysical Research Communications, 264(3), 759–762. https://doi.org/10.1006/bbrc.1999.1573.
Acknowledgements
Hereby the authors confirm that there is no conflict of interests in the present research. This research is supported financially by grant from Shahid Beheshti University.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hosseini, A., Khazali, H. Central Orexin A Affects Reproductive Axis by Modulation of Hypothalamic Kisspeptin/Neurokinin B/Dynorphin Secreting Neurons in the Male Wistar Rats. Neuromol Med 20, 525–536 (2018). https://doi.org/10.1007/s12017-018-8506-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12017-018-8506-x