Characterization of nociceptin hyperalgesia and allodynia in conscious mice

• Published in: British journal of pharmacology Vol. 121; no. 3; pp. 401 - 408
• Main Authors: Hara, Naoki, Minami, Toshiaki, Okuda‐Ashitaka, Emiko, Sugimoto, Tetsuo, Sakai, Masato, Onaka, Masahiko, Mori, Hidemaro, Imanishi, Toshihiro, Shingu, Koh, Ito, Seiji
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-06-1997; Nature Publishing
• Subjects: allodynia; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; glutamate; glycine; hyperalgesia; Hyperalgesia - chemically induced; Male; Mice; morphine; Morphine - pharmacology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - physiology; Nociceptin; Nociceptin Receptor; Opioid Peptides - pharmacology; Pain - chemically induced; Receptors, GABA - physiology; Receptors, Glycine - physiology; Receptors, Opioid - physiology; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; spinal cord; Vertebrates: nervous system and sense organs; Nociception; Allodynia; Spinal cord; Rodentia; Central nervous system; Morphine; Glutamate receptor; Intrathecal administration; Mechanism; Hyperalgesia; Vertebrata; Mammalia; Pain; Mouse; Somesthetic pathway; Animal; Glycine receptor; High dose; Comparative study
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701146

Intrathecal (i.t.) administration of nociceptin and high doses of morphine induced allodynia in response to innocuous tactile stimuli, and i.t. nociceptin evoked hyperalgesia in response to noxious thermal stimuli in conscious mice. Here we have characterized the nociceptin‐induced allodynia and compared it with the morphine‐induced allodynia and the nociceptin‐evoked hyperalgesia.
Nociceptin‐induced allodynia was evoked by the first stimulus 5 min after i.t. injection, reached a maximum at 10 min, and continued for a 50 min experimental period. Dose‐dependency of the allodynia showed a bell‐shaped pattern from 50 pg to 5 ng kg−1, and the maximum effect was observed at 2.5 ng kg−1.
Morphine‐induced allodynia reached the maximum effect at 15 min and declined progressively until cessation by 40–50 min. The dose‐response curve showed a bell‐shaped pattern, similar to that induced by nociceptin, with a maximum effect at 0.5 mg kg−1, five orders of magnitude higher than that of nociceptin.
The allodynia evoked by nociceptin and morphine were dose‐dependently blocked by glycine, D(−)‐2‐amino‐5‐phosphonovaleric acid (D‐AP5, an N‐methyl‐D‐aspartate (NMDA) receptor antagonist), γ‐D‐glutamylaminomethyl sulphonic acid (GAMS, a non‐NMDA receptor antagonist) and methylene blue (a soluble guanylate cyclase inhibitor), but were not affected by muscimol (a γ‐aminobutyric acidA (GABAA) receptor agonist) and baclofen (a GABAB receptor agonist).
Morphine did not inhibit forskolin‐stimulated cyclicAMP formation in cultured cells expressing the nociceptin receptor.
Nociceptin‐induced hyperalgesia was evoked 10–15 min after i.t. injection. Nociceptin produced a monophasic hyperalgesic action over a wide range of doses from 5 fg to 50 ng kg−1. The nociceptin‐induced hyperalgesia was blocked by glycine only among the agents examined.
None of the pain responses evoked by nociceptin and morphine were blocked by naloxone.
These results demonstrate that, whereas the mechanisms of the nociceptin‐induced allodynia and hyperalgesia are evidently distinct, they involve a common neurochemical event beginning with the disinhibition of the inhibitory glycinergic response. Morphine may induce allodynia through a pathway common to nociceptin, but the nociceptin receptor does not mediate the action of high doses of morphine.