The aim of the present study was to clarify the role of
nociceptin system in
pain modulation. The effects of the synthetic
nociceptin (NOP) receptor agonist,
Ro64-6198 ((1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one), on reactivity to acute noxious stimuli were assessed in C57BL/6N (B6) mice in tail-flick, hot-plate and
shock threshold tests. The
mu receptor agonist,
morphine, was used in each study for comparison. In the tail-flick test,
morphine (4 and 8 mg/kg, i.p.) produced
analgesia, while
Ro64-6198 (0.3, 1 and 3 mg/kg, i.p.) increased
pain sensitivity. The effects of
Ro64-6198 were seen in naïve but not in mice previously habituated to testing conditions, indicating that increased
pain sensitivity may be due to inhibition of stress-induced
analgesia. In the hot-plate and the
shock threshold tests,
Ro64-6198 produced
analgesia in B6 mice, like
morphine. These effects were reproduced in wild-type but not in NOP receptor knockout mice. Finally, when injected conjointly at subthreshold doses,
Ro64-6198 (1 mg/kg) and
morphine (1 mg/kg) acted in additive manner to reduce
pain sensitivity in the hot-plate test. Together these results show that systemic activation of NOP receptors produced bidirectional changes in
pain sensitivity depending on the experimental conditions. They also suggest that central NOP and
mu receptors may inhibit reactivity to acute noxious stimuli via independent neural mechanisms.