Effects of nociceptin/orphanin FQ receptor (NOP) agonist, Ro64-6198, on reactivity to acute pain in mice: comparison to morphine.
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.
Reiss
David
D
ICS, 1 Rue Laurent Fries, BP 10142, 67404 Illkirch, France.
Wichmann
Juergen
J
Tekeshima
Hiroshi
H
Kieffer
Brigitte L
BL
Ouagazzal
Abdel-Mouttalib
AM
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000819:agonists / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000819:agonists; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013312:Stress, Physiological; D013623:Tail; D000094942:Nociceptin Receptor
D000701:Analgesics, Opioid; D007093:Imidazoles; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C408068:Ro 64-6198; D013141:Spiro Compounds; D009020:Morphine; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse