RFRP 3 (human)

Seasonal control of reproduction is critical for the perpetuation of species living in temperate zones that display major changes in climatic environment and availability of food resources. In mammals, seasonal cues are mainly provided by the annual change in the 24-h light/dark ratio (i.e., photoperiod), which is translated into the nocturnal production of the pineal hormone melatonin. The annual rhythm in this melatonin signal acts as a synchronizer ensuring that breeding occurs when environmental conditions favor survival of the offspring. Although specific mechanisms might vary among seasonal species, the hypothalamic RF (Arg-Phe) amide-related peptides (RFRP-1 and -3) are believed to play a critical role in the central control of seasonal reproduction and in all seasonal species investigated, the RFRP system is persistently inhibited in short photoperiod. Central chronic administration of RFRP-3 in short day-adapted male Syrian hamsters fully reactivates the reproductive axis despite photoinhibitory conditions, which highlights the importance of the seasonal changes in RFRP expression for proper regulation of the reproductive axis. The acute effects of RFRP peptides, however, depend on species and photoperiod, and recent studies point toward a different role of RFRP in regulating female reproductive activity.

A novel RFamide peptide, gonadotropin-inhibitory hormone (GnIH) has emerged as a modulator of avian reproduction. However, the functional role of the mammalian homologue, RFRP-3 remains poorly understood. The RFRP-3 neuronal circuit is influenced by the stress axis. However, whether the Rfrp gene is under direct glucocorticoid (GC)-mediated transcriptional regulation, in the presence and absence of the gonadal steroid, 17β-estradiol, is unknown. We investigated the regulation of the Rfrp (GnIH) and Gpr147 (GnIH-R) transcripts by steroids in a novel hypothalamic Rfrp-expressing cell model, rHypoE-23. The GC agonist, dexamethasone increased Rfrp and Gpr147 mRNA levels. Dexamethasone acted directly on the nuclear GC receptor (GR) to mediate GC-dependent transcriptional changes, independently of de novo protein synthesis. 17β-estradiol had no significant effect on Rfrp or Gpr147 biosynthesis in these neurons. This suggests that Rfrp-expressing neurons serve as potential upstream mediators of stress-induced effects through GR-dependent mechanisms.

Neuropeptide FF receptors (NPFFR1 and NPFFR2) have been proposed to possess anti-opioid properties, and be involved in the development of opiate tolerance and dependence. However, there is no evidence to date supporting such opioid effects at the cellular level in vivo. Using in vivo electrophysiological recordings from vasopressin and oxytocin neurons in the supraoptic nucleus, we aimed to determine the effects of NPFFRs on opiate inhibition, tolerance, and dependence at a cellular level. Both vasopressin and oxytocin neurons are acutely inhibited by opioids and develop opiate tolerance. Oxytocin neurons also develop cellular opiate dependence and undergo withdrawal hyperexcitation upon cessation of opiate administration. Here, the classical μ-opioid receptor agonist, morphine robustly inhibited the spontaneous firing rate of vasopressin and oxytocin neurons, and this inhibition was attenuated by pretreatment with the NPFFR1 agonist, RFamide-related peptide-3. In rats infused with morphine for 6 d, vasopressin neurons were unresponsive to morphine, indicating the development of cellular tolerance, but pretreatment with the NPFFR antagonist, GJ14, restored acute morphine inhibition.