Our long-range goal is to compare the regulation of the newly identified opioid-like peptide, orphanin FQ (OFQ), and its receptor, ORL-1, with the regulation of other opioid peptides and their receptors and to determine their functional roles. Little is known at present concerning the functions or regulation of OFQ. We have recently shown that the level of OFQ mRNA in striatal cell cultures is markedly increased by depolarizing stimuli, forskolin, or certain neurotrophic factors including CNTF, LIF, BDNF and NT-3. OFQ and ORL-1 and their mRNAs are also found in cortical neurons and in dorsal root ganglia (DRG).
Four Specific Aims are proposed: (1) We will compare the regulation of OFQ and ORL-1 by depolarization, by forskolin, and by neurotrophic factors, in striatal, cortical and DRG neurons, and will delineate the second messenger pathways and transcription factors involved in the increase in OFQ expression. Similar studies will be conducted in immune cells since we have recently found that the mRNAs for OFQ and ORL-1 are expressed at relatively high concentrations by discrete populations of immune system cells. (2) We will test the hypothesis that OFQ causes activation of G proteins in cortical, striatal and DRG neurons in culture, and in ORL-1 expressing cells of the immune system, and that chronic exposure to OFQ can induce a desensitization to its actions in each of these systems. The observation that OFQ expression in brain is high from embryonic day 14 to birth, and that its expression is increased by neurotrophic factors suggests that OFQ may have developmental and neuroprotective roles. (3) We will test the hypothesis that OFQ is neurotrophic and neuroprotective in vitro. Finally (4), we will test the neuroprotective effects of OFQ in an in vivo model of excitotoxin-induced neural injury. Our expectation is that at the conclusion of the proposed studies we will have determined precisely those factors regulating the expression of OFQ in relation to other opioid peptides in the selected cell populations and will have identified tissue specific differences in its regulation if they occur. We will also have determined if heterologous desensitization between ORL-1 receptors and other opioid receptors occurs, an important issue in determining if agonists at ORL-1 receptors might be useful in regulating the functions of neurons tolerant to and dependent on mu receptor agonists. Finally, we will have evaluated the potential roles of OFQ and its receptor in the neurotrophic and neuroprotective actions of cytokines, and provided some insight into whether agonists at ORL-1 receptors might have therapeutic potential as neuroprotective agents.
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