1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (
SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective
nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]
guanosine 5'-O-(3-thiotriphosphate) assay in vitro,
SR14150 is a partial agonist at both the NOP and μ-
opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in
chronic pain, subsequent to spinal nerve
ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery,
SR14150 but not SR16835 increased tail-flick latency, which was blocked by the
opioid antagonist naloxone, but not by the NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). In contrast, both
SR14150 and SR16835 had antiallodynic activity when
mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by
SB-612111 but not by
naloxone. On the other hand,
morphine antinociception and antiallodynia were both blocked by
naloxone and potentiated by
SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and
chronic pain states is different. It is possible that during a
chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of
morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as
analgesics in
acute pain, they may have efficacy as
analgesics, either alone or in combination with
morphine, for treatment of
chronic pain.