Mills Richard H, Sohn Richard K, Micevych Paul E
Department of Neurobiology, David Geffen School of Medicine, Laboratory of Neuroendocrinology, Brain Research Institute, University of California, Los Angeles, California 90095, USA.
J Neurosci. 2004 Jan 28;24(4):947-55. doi: 10.1523/JNEUROSCI.1366-03.2004.
The endogenous peptides beta-endorphin (beta-END) and neuropeptide Y (NPY) have been implicated in regulating sexual receptivity. Both beta-END and NPY systems are activated by estrogen and inhibit female sexual receptivity. The initial estrogen-induced sexual nonreceptivity is correlated with the activation and internalization of mu-opioid receptors (MORs), in the medial preoptic nucleus (MPN). Progesterone reverses the estrogen-induced activation/internalization of MOR and induces the sexual receptive behavior lordosis. To determine whether NPY and endogenous opioids interact, we tested the hypothesis that estrogen-induced MOR activation is mediated through NPY-Y1 receptor (Y1R) activation. Retrograde tract tracing demonstrated Y1Ron beta-END neurons that projected to the MPN. Sex steroid modulation of MOR in the MPN acts through NPY and the Y1R. Estradiol administration or intracerebroventricular injection of NPY activated/internalized Y1R in the arcuate nucleus and MOR in the MPN of ovariectomized (OVX) rats. Moreover, the selective Y1R agonist [Leu31, Pro34]-Neuropeptide Y (LPNY) internalized MOR in the MPN of OVX rats. The Y1R antagonist (Cys31, Nva34)-Neuropeptide Y (27-36)2 prevented estrogen-induced Y1R and MOR activation/internalization. NPY reversed the progesterone blockade of estradiol-induced Y1R and MOR internalization in the arcuate nucleus and MPN, respectively. Behaviorally, LPNY inhibited estrogen plus progesterone-induced lordosis, and the MOR-selective antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr amide reversed LPNY-induced inhibition of lordosis. These results suggest that a sequential sex steroid activation of NPY and MOR circuits regulates sexual receptivity.
内源性肽类β-内啡肽（β-END）和神经肽Y（NPY）与调节性接受性有关。β-END和NPY系统均受雌激素激活，并抑制雌性的性接受性。雌激素最初诱导的性无接受性与内侧视前核（MPN）中μ-阿片受体（MORs）的激活和内化相关。孕酮可逆转雌激素诱导的MOR激活/内化，并诱导性接受行为——脊柱前凸。为了确定NPY与内源性阿片类物质是否相互作用，我们检验了雌激素诱导的MOR激活是通过NPY-Y1受体（Y1R）激活介导的这一假说。逆行束路追踪显示，投射至MPN的β-END神经元上存在Y1R。MPN中MOR的性类固醇调节通过NPY和Y1R发挥作用。给予雌二醇或脑室内注射NPY可激活/内化去卵巢（OVX）大鼠弓状核中的Y1R以及MPN中的MOR。此外，选择性Y1R激动剂[Leu31, Pro34]-神经肽Y（LPNY）可使OVX大鼠MPN中的MOR内化。Y1R拮抗剂（Cys31, Nva34）-神经肽Y（27-36）2可阻止雌激素诱导的Y1R和MOR激活/内化。NPY分别逆转了孕酮对雌二醇诱导的弓状核和MPN中Y1R和MOR内化的阻断作用。在行为学上，LPNY抑制了雌激素加孕酮诱导的脊柱前凸，而MOR选择性拮抗剂D-苯丙氨酸-半胱氨酸-酪氨酸-d-色氨酸-鸟氨酸-苏氨酸-青霉胺-苏氨酸酰胺可逆转LPNY诱导的脊柱前凸抑制作用。这些结果表明，NPY和MOR回路的性类固醇顺序激活调节了性接受性。
