Endocrine Role of OFQ/N: Studies with Knock-out Mice

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DESCRIPTION (provided by applicant): The hypothesis to be tested is that OFQ/N plays a physiologically significant role in the regulation of prolactin secretion and that it exerts this control at the hypothalamic level, specifically by inhibiting the tuberoinfundibular dopaminergic neurons. To accomplish this goal, male and female OFQIN knockout mice, and their wild type and heterozygous littermates, will be used in these proposed studies. The suckling-induced prolactin increase wifl be determined since suckling is a potent and important physiological stimulus for prolactin release. If OFQ/N is important for this response, then the suckling-induced increase will be attenuated in OFQ/N knockout mice. Furthermore, OFQIN administration will stimulate prolactin release and enhance the suckling-induced increase, even in knockouts because they still express the receptors. However, the possibility that compensatory mechanisms occur, e.g. due to the actions of other opiate peptides will be addressed by pretreating mice with opiate receptor antagonists or antiserum to eliminate each one of the other endogenous opiates. Sex differences in the sensitivity of the prolactin secretory response to OFQIN will be determined by conducting dose response studies in male and female mice. The ability of the OFQIN receptor to function in knockout mice, that develop and mature in the absence of the peptide, will be determined. Finally, the neural mechanism of action will be determined by quantifying specific amines, particularly dopamine, in the median eminence and other select regions of the brain.The iong term objective of this research is to understand the neural regulation of prolactin secretion, particularly the interaction among the different endogenous opiate peptides and their receptors. Prolactin has a number of important physiological roles. It is involved in reproduction, as well as being important in mediating the stress response, immunocompetence and maintaining homeostasis. To understand reproductive and stress-related disorders, it is important to understand the neurochemical regulation of prolactin release.