The hypothesis to be tested is that Orphanin FQ (OFQ) is involved in the physiological regulation of prolactin secretion and that this peptide's mechanism of action is at the hypothalamic level. Specifically, OFQ inhibits the activity of the tuberoinfundibular and tuberohypophyseal dopaminergic (TIDA and THDA, respectively) neurons, which produces a stimulatory effect on prolactin secretion. Furthermore, OFQ plays a physiological role in prolactin regulation and is involved in the suckling-induced prolactin increase. The hypothesis will be tested using several approaches in male and females rats. First, the mechanism of action will be examined by determining the neurochemical response to OFQ administration. DOPA accumulation will be used as index of dopaminergic activity and 5-hydroxytryptophan as an index of serotonergic activity in specific regions of the brain involved in prolactin regulation. Second, pharmacological specificity of the stimulatory effects of OFQ on prolactin release will be demonstrated by blocking this response with Acetyl-RYYRIK-NH2, an OFQ antagonist that has been shown to have antagonist activity in rat brain. Third, double-label immunocyto-chemical studies will determine the specific dopaminergic neurons in the arcuate nucleus that are inhibited by OFQ. Simultaneous expression of tyrosine hydroxylase and c-fos will be examined. Finally, the role of OFQ in mediating the suckling-induced prolactin increase will be determined by pretreated post-partum, lactating female rats with Acetyl-RYYRIK-NH2 prior to a suckling bout. The suckling-induced prolactin increase, as well as the suckling-induced inhibition of TIDA and THDA neurons and activation of serotonergic neurons, will be quantified. The long term objectives of this research are to understand the neural regulation of prolactin release and the interaction between the prolactin releasing and inhibiting factors in different physiological states, such as lactation, as well as gender differences in the regulation of this hormone. Prolactin has many important physiological roles. It can affect reproductive functions (e.g. hyperprolactinemia is associated with oligomenorrhea) and prolactin levels are affected by stress and exercise, which influences reproductive cyclicity. In order to understand reproductive disorders or disorders due to stress, it its important to understand the nature of the connections between the various and numerous factors regulating prolactin secretion.
| Kraska, Amy; Bryant, Winnifred; Murphree, Emily et al. (2005) Lack of involvement of dopamine and serotonin during the orphanin FQ/Nociceptin (OFQ/N)-induced prolactin secretory response. Life Sci 77:1465-79 |
