Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the Gi-coupled N/OFQ receptor (NOP). We have examined the effects of\ud chronic exposure of Chinese hamster ovary cells expressing the recombinant human NOP receptor (CHOhNOP) to 1 nM N/OFQ for up to 48 h\ud in the absence and presence of the NOP selective antagonist [Nphe1]N/OFQ (1–13)NH2 ([Nphe1]). Then, either a concentration–response\ud curve for N/OFQ inhibition of cAMP formation was constructed or the cells were homogenized and membrane receptor density was\ud determined using [125I]Y14N/OFQ. There was a time-dependent reduction in pEC50 (without a change in maximum) for N/OFQ with\ud significant differences observed following > 24 h of exposure (control pEC50f9.5; 48 h pretreatmentf8.7). In cells co-exposed to N/\ud OFQ+[Nphe1] for 48 h, there was no reduction in pEC50. There was a compensatory (f2.5-fold), [Nphe1]-sensitive increase in cAMP mass\ud in cells exposed to N/OFQ for 24–48 h. N/OFQ pretreatment also resulted in a time-dependent [Nphe1]-sensitive loss of cell surface\ud receptors. At 48 h, Bmax was reduced from f2.0 to f1.3 pmol mg1 protein without a change in pKd for N/OFQ. There was a positive\ud correlation between pEC50 for cAMP inhibition and Bmax. The lack of effect on maximum cAMP response probably results from receptor\ud overexpression and the creation of a receptor reserve
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