The
nociceptin receptor (NOPr), a member of the
opioid receptor family, is a target for the treatment of
pain and
drug abuse.
Nociceptin/orphanin FQ (N/OFQ), the endogenous
peptide for NOPr, not only modulates
opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as
morphine,
cocaine, and
amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the
mu-opioid receptor (MOPr), may function as nonaddicting
analgesics or as
drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (
CPP) and their effect on
morphine-induced
CPP. 1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one) (
SR14150), a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced
analgesia that was
naloxone-reversible.
SR14150 did not induce
CPP alone, nor did it attenuate
morphine-induced
CPP. 3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, and partial agonist activity at MOPr, was also a potent
analgesic and produced
CPP alone, but also modestly attenuated
morphine CPP. 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce
CPP alone, but attenuated
morphine CPP. Our results suggest that NOPr full-agonist activity is required to modulate
opioid-induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a nonaddicting
analgesic. The
opioid-modulating effects of the NOPr
ligands may be used effectively to produce better medications for treatment of
drug abuse and
pain.