1. 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. 2.
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. 3.
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. 4. 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), gamma-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 gamma-aminobutyric acidA (GABAA) receptor agonist) and
baclofen (a GABAB receptor agonist). 5.
Morphine did not inhibit
forskolin-stimulated cyclicAMP formation in cultured cells expressing the
nociceptin receptor. 6.
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. 7. None of the
pain responses evoked by
nociceptin and
morphine were blocked by
naloxone. 8. 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.