Novel Biology of Tachykinins in Gonadotropin-Releasing Hormone Secretion

Abstract

The tachykinin family of peptides, composed of the neurokinins A and B (NKA, NKB) and substance P are involved in the central control of gonadotropin-releasing hormone (GnRH) release through a variety of neuronal circuitries that mediate the activation of Kiss1 neurons and the synchronization of their activity within the arcuate nucleus. The major outcome of this role is the precise regulation of the pulsatile pattern of GnRH release. In addition, tachykinins are involved in the maturation of the reproductive axis by determining the optimal timing of puberty onset, as well as in the timing of the preovulatory luteinizing hormone surge in females. Therefore, the action of tachykinins in reproduction appears to extend to all the critical aspects required for the successful attainment and maintenance of fertility. In this review, we summarize the latest advances in our understanding of the biology of tachykinins in the control of GnRH release, addressing the existing controversies, open questions, and future perspectives.

Keywords

tachykinins - GnRH - kisspeptin - hypothalamus - reproduction

Disclosures

The authors have nothing to disclose.

• References

• 1 Topaloglu AK, Reimann F, Guclu M. , et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41 (03) 354-358
• 2 Chawla MK, Gutierrez GM, Young III WS, McMullen NT, Rance NE. Localization of neurons expressing substance P and neurokinin B gene transcripts in the human hypothalamus and basal forebrain. J Comp Neurol 1997; 384 (03) 429-442
• 3 Danzer SC, Price RO, McMullen NT, Rance NE. Sex steroid modulation of neurokinin B gene expression in the arcuate nucleus of adult male rats. Brain Res Mol Brain Res 1999; 66 (1-2): 200-204
• 4 Rance NE, Bruce TR. Neurokinin B gene expression is increased in the arcuate nucleus of ovariectomized rats. Neuroendocrinology 1994; 60 (04) 337-345
• 5 Rance NE, Young III WS. Hypertrophy and increased gene expression of neurons containing neurokinin-B and substance-P messenger ribonucleic acids in the hypothalami of postmenopausal women. Endocrinology 1991; 128 (05) 2239-2247
• 6 Wenk GL, Rance NE, Mobley SL. Effects of excitatory amino acid lesions upon neurokinin B and acetylcholine neurons in the nucleus basalis of the rat. Brain Res 1995; 679 (01) 8-14
• 7 Fergani C, Navarro VM. Expanding the role of tachykinins in the neuroendocrine control of reproduction. Reproduction 2016; 153 (01) R1-R14
• 8 Steinhoff MS, von Mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev 2014; 94 (01) 265-301
• 9 Polak JM, Bloom SR. The peripheral substance P-ergic system. Peptides 1981; 2 (Suppl. 02) 133-148
• 10 Maggi CA. The troubled story of tachykinins and neurokinins. Trends Pharmacol Sci 2000; 21 (05) 173-175
• 11 Rønnekleiv OK, Kelly MJ, Eskay RL. Distribution of immunoreactive substance P neurons in the hypothalamus and pituitary of the rhesus monkey. J Comp Neurol 1984; 224 (01) 51-59
• 12 Tsuruo Y, Hisano S, Okamura Y, Tsukamoto N, Daikoku S. Hypothalamic substance P-containing neurons. Sex-dependent topographical differences and ultrastructural transformations associated with stages of the estrous cycle. Brain Res 1984; 305 (02) 331-341
• 13 Kerdelhué B, Tartar A, Lenoir V, el Abed A, Hublau P, Millar RP. Binding studies of substance P anterior pituitary binding sites: changes in substance P binding sites during the rat estrous cycle. Regul Pept 1985; 10 (2-3): 133-143
• 14 Makara GB, Kakucska I, Lenoir V, Kerdelhue B, Palkovits M. A substance P-containing hypothalamic neuronal system projects to the median eminence. Brain Res 1986; 374 (02) 399-401
• 15 Ohtsuka S, Miyake A, Nishizaki T, Tasaka K, Aono T, Tanizawa O. Substance P stimulates gonadotropin-releasing hormone release from rat hypothalamus in vitro with involvement of oestrogen. Acta Endocrinol (Copenh) 1987; 115 (02) 247-252
• 16 Arisawa M, De Palatis L, Ho R. , et al. Stimulatory role of substance P on gonadotropin release in ovariectomized rats. Neuroendocrinology 1990; 51 (05) 523-529
• 17 Tsuruo Y, Kawano H, Hisano S. , et al. Substance P-containing neurons innervating LHRH-containing neurons in the septo-preoptic area of rats. Neuroendocrinology 1991; 53 (03) 236-245
• 18 Coiro V, Volpi R, Capretti L. , et al. Luteinizing hormone response to an intravenous infusion of substance P in normal men. Metabolism 1992; 41 (07) 689-691
• 19 Shamgochian MD, Leeman SE. Substance P stimulates luteinizing hormone secretion from anterior pituitary cells in culture. Endocrinology 1992; 131 (02) 871-875
• 20 Traczyk WZ, Pau KY, Kaynard AH, Spies HG. Modulatory role of substance P on gonadotropin and prolactin secretion in the rabbit. J Physiol Pharmacol 1992; 43 (03) 279-297
• 21 de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
• 22 Seminara SB, Messager S, Chatzidaki EE. , et al. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349 (17) 1614-1627
• 23 Herbison AE. Physiology of the GnRH neuronal network. In: Knobil E, Neill J. , eds. Physiology of Reproduction. San Diego, CA: Academic Press; 2006: 1415-1482
• 24 Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 2005; 146 (09) 3686-3692
• 25 Smith JT, Dungan HM, Stoll EA. , et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005; 146 (07) 2976-2984
• 26 Navarro VM, Bosch MA, León S. , et al. The integrated hypothalamic tachykinin-kisspeptin system as a central coordinator for reproduction. Endocrinology 2015; 156 (02) 627-637
• 27 León S, Fergani C, Talbi R. , et al. Characterization of the role of NKA in the control of puberty onset and gonadotropin release in the female mouse. Endocrinology 2019; 160 (10) 2453-2463
• 28 Navarro VM, Castellano JM, McConkey SM. , et al. Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am J Physiol Endocrinol Metab 2011; 300 (01) E202-E210
• 29 Parnet P, Mitsuhashi M, Turck CW, Kerdelhue B, Payan DG. Tachykinin receptor cross-talk. Immunological cross-reactivity between the external domains of the substance K and substance P receptors. Brain Behav Immun 1991; 5 (01) 73-83
• 30 Grachev P, Li XF, Lin YS. , et al. GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats. PLoS One 2012; 7 (09) e44344
• 31 Navarro VM, Gottsch ML, Wu M. , et al. Regulation of NKB pathways and their roles in the control of Kiss1 neurons in the arcuate nucleus of the male mouse. Endocrinology 2011; 152 (11) 4265-4275
• 32 Navarro VM, Ruiz-Pino F, Sánchez-Garrido MA. , et al. Role of neurokinin B in the control of female puberty and its modulation by metabolic status. J Neurosci 2012; 32 (07) 2388-2397
• 33 Ruiz-Pino F, Garcia-Galiano D, Manfredi-Lozano M. , et al. Effects and interactions of tachykinins and dynorphin on FSH and LH secretion in developing and adult rats. Endocrinology 2015; 156 (02) 576-588
• 34 Ruiz-Pino F, Navarro VM, Bentsen AH. , et al. Neurokinin B and the control of the gonadotropic axis in the rat: developmental changes, sexual dimorphism, and regulation by gonadal steroids. Endocrinology 2012; 153 (10) 4818-4829
• 35 Ahn T, Fergani C, Coolen LM, Padmanabhan V, Lehman MN. Prenatal testosterone excess decreases neurokinin 3 receptor immunoreactivity within the arcuate nucleus KNDy cell population. J Neuroendocrinol 2015; 27 (02) 100-110
• 36 Amstalden M, Coolen LM, Hemmerle AM. , et al. 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. J Neuroendocrinol 2010; 22 (01) 1-12
• 37 Billings HJ, Connors JM, Altman SN. , et al. Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology 2010; 151 (08) 3836-3846
• 38 Goodman RL, Coolen LM, Lehman MN. A role for neurokinin B in pulsatile GnRH secretion in the ewe. Neuroendocrinology 2014; 99 (01) 18-32
• 39 Goodman RL, Hileman SM, Nestor CC. , et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology 2013; 154 (11) 4259-4269
• 40 Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM. Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. Endocrinology 2012; 153 (06) 2756-2765
• 41 Wakabayashi Y, Nakada T, Murata K. , et al. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J Neurosci 2010; 30 (08) 3124-3132
• 42 Wakabayashi Y, Yamamura T, Sakamoto K, Mori Y, Okamura H. Electrophysiological and morphological evidence for synchronized GnRH pulse generator activity among Kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in goats. J Reprod Dev 2013; 59 (01) 40-48
• 43 Yamamura T, Wakabayashi Y, Ohkura S, Navarro VM, Okamura H. Effects of intravenous administration of neurokinin receptor subtype-selective agonists on gonadotropin-releasing hormone pulse generator activity and luteinizing hormone secretion in goats. J Reprod Dev 2015; 61 (01) 20-29
• 44 Nakamura S, Wakabayashi Y, Yamamura T, Ohkura S, Matsuyama S. A neurokinin 3 receptor-selective agonist accelerates pulsatile luteinizing hormone secretion in lactating cattle. Biol Reprod 2017; 97 (01) 81-90
• 45 Garcia JP, Guerriero KA, Keen KL, Kenealy BP, Seminara SB, Terasawa E. Kisspeptin and neurokinin B signaling network underlies the pubertal increase in GnRH release in female rhesus monkeys. Endocrinology 2017; 158 (10) 3269-3280
• 46 Garcia JP, Keen KL, Kenealy BP, Seminara SB, Terasawa E. Role of kisspeptin and neurokinin B signaling in male rhesus monkey puberty. Endocrinology 2018; 159 (08) 3048-3060
• 47 Ramaswamy S, Seminara SB, Ali B, Ciofi P, Amin NA, Plant TM. Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology 2010; 151 (09) 4494-4503
• 48 Narayanaswamy S, Prague JK, Jayasena CN. , et al. Investigating the KNDy hypothesis in humans by coadministration of kisspeptin, neurokinin B, and naltrexone in men. J Clin Endocrinol Metab 2016; 101 (09) 3429-3436
• 49 Jayasena CN, Comninos AN, De Silva A. , et al. Effects of neurokinin B administration on reproductive hormone secretion in healthy men and women. J Clin Endocrinol Metab 2014; 99 (01) E19-E27
• 50 Fraser GL, Hoveyda HR, Clarke IJ. , et al. The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology 2015; 156 (11) 4214-4225
• 51 Skorupskaite K, George JT, Veldhuis JD, Anderson RA, Neurokinin B. Neurokinin B regulates gonadotropin secretion, ovarian follicle growth, and the timing of ovulation in healthy women. J Clin Endocrinol Metab 2018; 103 (01) 95-104
• 52 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 receptor antagonism decreases gonadotropin and testosterone secretion in healthy men. Clin Endocrinol (Oxf) 2017; 87 (06) 748-756
• 53 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 receptor antagonism reveals roles for neurokinin B in the regulation of gonadotropin secretion and hot flashes in postmenopausal women. Neuroendocrinology 2018; 106 (02) 148-157
• 54 Fergani C, Mazzella L, Coolen LM. , et al. Do substance P and neurokinin A play important roles in the control of LH secretion in ewes?. Endocrinology 2016; 157 (12) 4829-4841
• 55 Kalil B, Ramaswamy S, Plant TM. The distribution of substance P and kisspeptin in the mediobasal hypothalamus of the male rhesus monkey and a comparison of intravenous administration of these peptides to release GnRH as reflected by LH secretion. Neuroendocrinology 2016; 103 (06) 711-723
• 56 Young J, Bouligand J, Francou B. , et al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 2010; 95 (05) 2287-2295
• 57 Day FR, Perry JR, Ong KK. Genetic regulation of puberty timing in humans. Neuroendocrinology 2015; 102 (04) 247-255
• 58 Maguire CA, Song YB, Wu M. , et al. Tac1 signaling is required for sexual maturation and responsiveness of GnRH neurons to kisspeptin in the male mouse. Endocrinology 2017; 158 (07) 2319-2329
• 59 Simavli S, Thompson IR, Maguire CA. , et al. Substance P regulates puberty onset and fertility in the female mouse. Endocrinology 2015; 156 (06) 2313-2322
• 60 True C, Nasrin Alam S, Cox K, Chan YM, Seminara SB. Neurokinin B is critical for normal timing of sexual maturation but dispensable for adult reproductive function in female mice. Endocrinology 2015; 156 (04) 1386-1397
• 61 Yang JJ, Caligioni CS, Chan YM, Seminara SB. Uncovering novel reproductive defects in neurokinin B receptor null mice: closing the gap between mice and men. Endocrinology 2012; 153 (03) 1498-1508
• 62 Gianetti E, Tusset C, Noel SD. , et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J Clin Endocrinol Metab 2010; 95 (06) 2857-2867
• 63 Goodman RL, Lehman MN, Smith JT. , et al. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 2007; 148 (12) 5752-5760
• 64 Hrabovszky E, Borsay BA, Rácz K. , et al. Substance P immunoreactivity exhibits frequent colocalization with kisspeptin and neurokinin B in the human infundibular region. PLoS One 2013; 8 (08) e72369
• 65 Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 2009; 29 (38) 11859-11866
• 66 Abbara A, Clarke S, Islam R. , et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a Phase 2 randomized controlled trial. Hum Reprod 2017; 32 (09) 1915-1924
• 67 Fergani C, Newcomb N, Goodman RL, Coolen LM, Lehman M. Anatomical relationships of kisspeptin to substance P and Neurokinin-1 receptor in the sheep arcuate nucleus. Paper presented at the Endocrine Society Annual Meeting; 2015; San Diego, CA
• 68 Okamura H, Yamamura T, Wakabayashi Y. Mapping of KNDy neurons and immunohistochemical analysis of the interaction between KNDy and substance P neural systems in goat. J Reprod Dev 2017; 63 (06) 571-580
• 69 Borsay BA, Skrapits K, Herczeg L. , et al. Hypophysiotropic gonadotropin-releasing hormone projections are exposed to dense plexuses of kisspeptin, neurokinin B and substance p immunoreactive fibers in the human: a study on tissues from postmenopausal women. Neuroendocrinology 2014; 100 (2-3): 141-152
• 70 Ramaswamy S, Seminara SB, Plant TM. Evidence from the agonadal juvenile male rhesus monkey (Macaca mulatta) for the view that the action of neurokinin B to trigger gonadotropin-releasing hormone release is upstream from the kisspeptin receptor. Neuroendocrinology 2011; 94 (03) 237-245
• 71 Gill JC, Navarro VM, Kwong C. , et al. Increased neurokinin B (Tac2) expression in the mouse arcuate nucleus is an early marker of pubertal onset with differential sensitivity to sex steroid-negative feedback than Kiss1. Endocrinology 2012; 153 (10) 4883-4893
• 72 Li SY, Li XF, Hu MH. , et al. Neurokinin B receptor antagonism decreases luteinising hormone pulse frequency and amplitude and delays puberty onset in the female rat. J Neuroendocrinol 2014; 26 (08) 521-527
• 73 Nakahara T, Uenoyama Y, Iwase A. , et al. Chronic peripheral administration of kappa-opioid receptor antagonist advances puberty onset associated with acceleration of pulsatile luteinizing hormone secretion in female rats. J Reprod Dev 2013; 59 (05) 479-484
• 74 Navarro VM, Tena-Sempere M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat Rev Endocrinol 2011; 8 (01) 40-53
• 75 Knobil E. On the control of gonadotropin secretion in the rhesus monkey. Recent Prog Horm Res 1974; 30 (00) 1-46
• 76 Plant TM. The neurobiological mechanism underlying hypothalamic GnRH pulse generation: the role of kisspeptin neurons in the arcuate nucleus. F1000 Res 2019; 8: 8
• 77 Irwig MS, Fraley GS, Smith JT. , et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 2004; 80 (04) 264-272
• 78 Li Q, Millar RP, Clarke IJ, Smith JT. Evidence that neurokinin B controls basal gonadotropin-releasing hormone secretion but is not critical for estrogen-positive feedback in sheep. Neuroendocrinology 2015; 101 (02) 161-174
• 79 Endo N, Tanaka T. Effects of senktide, a neurokinin 3 receptor agonist, on luteinizing hormone secretion and follicular development in anestrous Shiba goats: a pilot study. BMC Res Notes 2014; 7: 773
• 80 Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Interactions between neurokinin B and kisspeptin in mediating estrogen feedback in healthy women. J Clin Endocrinol Metab 2016; 101 (12) 4628-4636
• 81 Clarkson J, Han SY, Piet R. , et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc Natl Acad Sci U S A 2017; 114 (47) E10216-E10223
• 82 Murakawa H, Iwata K, Takeshita T, Ozawa H. Immunoelectron microscopic observation of the subcellular localization of kisspeptin, neurokinin B and dynorphin A in KNDy neurons in the arcuate nucleus of the female rat. Neurosci Lett 2016; 612: 161-166
• 83 Hassaneen A, Naniwa Y, Suetomi Y. , et al. Immunohistochemical characterization of the arcuate kisspeptin/neurokinin B/dynorphin (KNDy) and preoptic kisspeptin neuronal populations in the hypothalamus during the estrous cycle in heifers. J Reprod Dev 2016; 62 (05) 471-477
• 84 Krajewski SJ, Burke MC, Anderson MJ, McMullen NT, Rance NE. Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat. Neuroscience 2010; 166 (02) 680-697
• 85 Overgaard A, Ruiz-Pino F, Castellano JM, Tena-Sempere M, Mikkelsen JD. Disparate changes in kisspeptin and neurokinin B expression in the arcuate nucleus after sex steroid manipulation reveal differential regulation of the two KNDy peptides in rats. Endocrinology 2014; 155 (10) 3945-3955
• 86 Burke MC, Letts PA, Krajewski SJ, Rance NE. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol 2006; 498 (05) 712-726
• 87 Qiu J, Nestor CC, Zhang C. , et al. High-frequency stimulation-induced peptide release synchronizes arcuate kisspeptin neurons and excites GnRH neurons. eLife 2016; 5: 5
• 88 Ikegami K, Minabe S, Ieda N. , et al. Evidence of involvement of neurone-glia/neurone-neurone communications via gap junctions in synchronised activity of KNDy neurones. J Neuroendocrinol 2017 29(06):
• 89 Lippincott MF, León S, Chan YM. , et al. Hypothalamic reproductive endocrine pulse generator activity independent of neurokinin B and dynorphin signaling. J Clin Endocrinol Metab 2019; 104 (10) 4304-4318
• 90 Porter KL, Hileman SM, Hardy SL, Nestor CC, Lehman MN, Goodman RL. Neurokinin-3 receptor activation in the retrochiasmatic area is essential for the full pre-ovulatory luteinising hormone surge in ewes. J Neuroendocrinol 2014; 26 (11) 776-784
• 91 Grachev P, Porter KL, Coolen LM. , et al. Surge-like luteinising hormone secretion induced by retrochiasmatic area NK3R activation is mediated primarily by arcuate kisspeptin neurones in the ewe. J Neuroendocrinol 2016 28(06):
• 92 Merkley CM, Porter KL, Coolen LM. , et al. KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology 2012; 153 (11) 5406-5414
• 93 Fergani C, Routly JE, Jones DN, Pickavance LC, Smith RF, Dobson H. KNDy neurone activation prior to the LH surge of the ewe is disrupted by LPS. Reproduction 2017; 154 (03) 281-292
• 94 Mittelman-Smith MA, Krajewski-Hall SJ, McMullen NT, Rance NE. Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced LH surge in female rats. Endocrinology 2016; 157 (05) 2015-2027
• 95 Zhang Q, McCoy JM, Gallo RV. Further studies on possible dynorphin involvement in the ovulatory luteinizing hormone surge in the proestrous rat. Endocrine 2002; 18 (03) 231-238
• 96 Zhang Q, Gallo RV. Effect of prodynorphin-derived opioid peptides on the ovulatory luteinizing hormone surge in the proestrous rat. Endocrine 2002; 18 (01) 27-32
• 97 Battmann T, Mĕlik Parsadaniantz S, Jeanjean B, Kerdelhué B. In-vivo inhibition of the preovulatory LH surge by substance P and in-vitro modulation of gonadotrophin-releasing hormone-induced LH release by substance P, oestradiol and progesterone in the female rat. J Endocrinol 1991; 130 (02) 169-175
• 98 Duval P, Lenoir V, Garret C, Kerdelhue B. Reduction of the amplitude of preovulatory LH and FSH surges and of the amplitude of the in vitro GnRH-induced LH release by substance P. Reversal of the effect by RP 67580. Neuropharmacology 1996; 35 (12) 1805-1810
• 99 Kerdelhué B, Williams RF, Lenoir V. , et al. Variations in plasma levels of substance P and effects of a specific substance P antagonist of the NK(1) receptor on preovulatory LH and FSH surges and progesterone secretion in the cycling cynomolgus monkey. Neuroendocrinology 2000; 71 (04) 228-236
• 100 Krajewski SJ, Anderson MJ, Iles-Shih L, Chen KJ, Urbanski HF, Rance NE. Morphologic evidence that neurokinin B modulates gonadotropin-releasing hormone secretion via neurokinin 3 receptors in the rat median eminence. J Comp Neurol 2005; 489 (03) 372-386
• 101 Hrabovszky E, Ciofi P, Vida B. , et al. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci 2010; 31 (11) 1984-1998
• 102 Hrabovszky E, Sipos MT, Molnár CS. , et al. Low degree of overlap between kisspeptin, neurokinin B, and dynorphin immunoreactivities in the infundibular nucleus of young male human subjects challenges the KNDy neuron concept. Endocrinology 2012; 153 (10) 4978-4989
• 103 Fergani C, Leon S, Padilla SL, Verstegen AM, Palmiter RD, Navarro VM. NKB signaling in the posterodorsal medial amygdala stimulates gonadotropin release in a kisspeptin-independent manner in female mice. eLife 2018; 7: 7
• 104 Glidewell-Kenney CA, Shao PP, Iyer AK, Grove AM, Meadows JD, Mellon PL. Neurokinin B causes acute GnRH secretion and repression of GnRH transcription in GT1-7 GnRH neurons. Mol Endocrinol 2013; 27 (03) 437-454
• 105 Gaskins GT, Glanowska KM, Moenter SM. Activation of neurokinin 3 receptors stimulates GnRH release in a location-dependent but kisspeptin-independent manner in adult mice. Endocrinology 2013; 154 (11) 3984-3989
• 106 García-Galiano D, van Ingen Schenau D, Leon S. , et al. Kisspeptin signaling is indispensable for neurokinin B, but not glutamate, stimulation of gonadotropin secretion in mice. Endocrinology 2012; 153 (01) 316-328
• 107 Holder MK, Mong JA. The role of ovarian hormones and the medial amygdala in sexual motivation. Curr Sex Health Rep 2017; 9 (04) 262-270
• 108 Cascieri MA, Huang RR, Fong TM. , et al. Determination of the amino acid residues in substance P conferring selectivity and specificity for the rat neurokinin receptors. Mol Pharmacol 1992; 41 (06) 1096-1099
• 109 Hökfelt T, Pernow B, Nilsson G, Wetterberg L, Goldstein M, Jeffcoate SL. Dense plexus of substance P immunoreactive nerve terminals in eminentia medialis of the primate hypothalamus. Proc Natl Acad Sci U S A 1978; 75 (02) 1013-1015
• 110 Maguire CA, León S, Carroll RS, Kaiser UB, Navarro VM. Altered circadian feeding behavior and improvement of metabolic syndrome in obese Tac1-deficient mice. Int J Obes 2017; 41 (12) 1798-1804
• 111 Abel TW, Voytko ML, Rance NE. The effects of hormone replacement therapy on hypothalamic neuropeptide gene expression in a primate model of menopause. J Clin Endocrinol Metab 1999; 84 (06) 2111-2118
• 112 Rance NE. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 2009; 30 (01) 111-122
• 113 Padilla SL, Johnson CW, Barker FD, Patterson MA, Palmiter RD. A neural circuit underlying the generation of hot flushes. Cell Rep 2018; 24 (02) 271-277
• 114 Rance NE, Dacks PA, Mittelman-Smith MA, Romanovsky AA, Krajewski-Hall SJ. Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes. Front Neuroendocrinol 2013; 34 (03) 211-227
• 115 Taziaux M, Swaab DF, Bakker J. Sex differences in the neurokinin B system in the human infundibular nucleus. J Clin Endocrinol Metab 2012; 97 (12) E2210-E2220
• 116 Vink R, van den Heuvel C. Substance P antagonists as a therapeutic approach to improving outcome following traumatic brain injury. Neurotherapeutics 2010; 7 (01) 74-80
• 117 Zacest AC, Vink R, Manavis J, Sarvestani GT, Blumbergs PC. Substance P immunoreactivity increases following human traumatic brain injury. Acta Neurochir Suppl (Wien) 2010; 106: 211-216
• 118 Blendonohy PM, Philip PA. Precocious puberty in children after traumatic brain injury. Brain Inj 1991; 5 (01) 63-68
• 119 Kaulfers AM, Backeljauw PF, Reifschneider K. , et al. Endocrine dysfunction following traumatic brain injury in children. J Pediatr 2010; 157 (06) 894-899
• 120 Sockalosky JJ, Kriel RL, Krach LE, Sheehan M. Precocious puberty after traumatic brain injury. J Pediatr 1987; 110 (03) 373-377