Opioid-Dopamine Interactions During Lactation

描述（由申请人提供）：哺乳是哺乳动物特有的生殖过程，对其生存至关重要。虽然母乳对人类的生存并不重要，但它被认为是新生儿的最佳营养。催乳素（prolacactin， PRL）是一种垂体前叶激素，影响哺乳的许多方面，包括母体行为、乳腺发育/分化和乳蛋白的产生。PRL水平的升高对于泌乳是必要的。PRL分泌增加的最初信号是新生儿的哺乳。该信号通过特定的神经通路通过脊髓和脑干传递到下丘脑，在那里它作用于神经元以增加PRL的释放并维持正常的泌乳。下丘脑的结节基底多巴胺能（TIDA）神经元对PRL释放提供主要抑制作用。泌乳期间，TIDA神经元活动受到抑制，导致PRL水平升高。内源性阿片肽是神经元网络中将哺乳刺激转化为PRL分泌增加的重要组成部分。这些阿片肽有助于抑制哺乳期间的TIDA神经元活动。然而，我们不了解多巴胺能神经元响应哺乳刺激时发生的细胞/分子过程，以及阿片肽如何与多巴胺能神经元相互作用以影响这些过程。第一个具体目标将通过评估酪氨酸羟化酶蛋白的磷酸化状态和酪氨酸羟化酶基因在哺乳刺激下的转录率来评估TIDA神经元中酪氨酸羟化酶的细胞调控。第二个特定目标将评估特定阿片受体亚型在TIDA神经元内的共定位和阿片受体在哺乳刺激下的表达。第三个具体目的是通过选择性阿片受体拮抗剂研究参与控制PRL分泌和TIDA神经元活性的阿片受体亚型。总的来说，这些研究将有助于我们理解与维持泌乳有关的复杂神经通路。

DESCRIPTION (provided by applicant): Lactation is a reproductive process, which is unique to mammalian species and essential for their survival. Although not critical for human survival, breast milk is considered the optimal nourishment for newborns. Prolactin (PRL) is an anterior pituitary hormone which influences many aspects of lactation including maternal behavior, mammary gland development/ differentiation and the production of milk proteins. Elevated PRL levels are essential for adequate lactation. The initial signal for increased PRL secretion is the suckling of the newborn. The signal is transmitted by a specific neural pathway through the spinal cord and brainstem to the hypothalamus where it acts on neurons to increase PRL release and maintain competent lactation. Tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus provide the primary inhibitory influence on PRL release. TIDA neuronal activity is suppressed during lactation, contributing to the elevated levels of PRL. The endogenous opioid peptides are an important component in the neuronal network to translate the suckling stimulus into increased PRL secretion. These opioid peptides contribute to the suppression of TIDA neuronal activity during lactation. However, we do not understand the cellular/molecular processes occurring in the dopaminergic neurons in response to the suckling stimulus and how opioid peptides interact with the dopaminergic neurons to influence these processes. The first specific aim will assess the cellular regulation of tyrosine hydroxylase in TIDA neurons by evaluating the phosphorylation state of tyrosine hydroxylase protein and transcriptional rate for tyrosine hydroxylase gene in response to the suckling stimulus. The second specific aim will evaluate the co-localization of particular opioid receptor subtypes within the TIDA neurons and opioid receptor expression in response to the suckling stimulus. The third specific aim will investigate opioid receptor subtype(s) involved in the control of PRL secretion and TIDA neuronal activity by using selective opioid receptor antagonists. Overall these studies will contribute to our understanding of the complex neuronal pathways involved in maintaining lactation.