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 ®rst 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 71 , and the maximum e ect was observed at 2.5 ng kg 71 . 3 Morphine-induced allodynia reached the maximum e ect 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 e ect at 0.5 mg kg 71 , ®ve orders of magnitude higher than that of nociceptin. 4 The allodynia evoked by nociceptin and morphine were dose-dependently blocked by glycine, D(7)-2-amino-5-phosphonovaleric acid (D-AP5, an N-methyl-D-aspartate (NMDA) receptor antagonist), g-Dglutamylaminomethyl sulphonic acid (GAMS, a non-NMDA receptor antagonist) and methylene blue (a soluble guanylate cyclase inhibitor), but were not a ected by muscimol (a g-aminobutyric acid A (GABA A ) receptor agonist) and baclofen (a GABA B 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 71 . The nociceptininduced 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.

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Prostacyclin (PGI2) is well known to play crucial roles in induction of edema and pain behavior in the periphery. In the present study, we investigated the central role of PGI2 in inflammatory pain. Intraplantar injection of carrageenan markedly induced the expression of prostacyclin receptor (IP receptor) mRNA with the maximum at 6 h, coincidently induction of the inducible form of cyclooxygenase (COX-2), although IP receptor mRNA was weakly expressed in the spinal cord of naive mice. Intrathecal administration of the IP agonist cicaprost induced mechanical hyperalgesia 6 h after carrageenan injection. These results suggest that PGI2 is involved in pain transmission at the spinal cord following expression of IP receptor mRNA induced by peripheral inflammation.

1 We recently showed that intrathecal administration of nociceptin induced allodynia by innocuous tactile stimuli and hyperalgesia by noxious thermal stimuli in conscious mice. In the present study, we examined the e ect of prostaglandins on nociceptin-induced allodynia and hyperalgesia. 2 Prostaglandin D 2 (PGD 2 ) blocked the allodynia induced by nociceptin in a dose-dependent manner with an IC 50 of 26 ng kg 71 , but did not a ect the nociceptin-induced hyperalgesia at doses up to 500 ng kg 71 . BW 245C (an agonist for PGD (DP) receptor) blocked the allodynia with an IC 50 of 83 ng kg 71 . 3 The blockade of nociceptin-induced allodynia by PGD 2 was reversed by the potent and selective DPreceptor antagonist BW A868C in a dose-dependent manner with an ED 50 of 42.8 ng kg 71 . 4 Glycine (500 ng kg 71 ) almost completely blocked the nociceptin-induced allodynia. A synergistic e ect on the inhibition of nociceptin-evoked allodynia was observed between glycine and PGD 2 at below e ective doses. 5 Dibutyryl cyclic AMP, but not dibutyryl cyclic GMP, blocked the nociceptin-induced allodynia with an IC 50 of 2.9 mg kg 71 . 6 PGE 2 , PGF 2a , butaprost (an EP 2 agonist) and cicaprost (a PGI receptor agonist) did not a ect the nociceptin-induced allodynia. 7 These results demonstrate that PGD 2 inhibits the nociceptin-evoked allodynia through DP receptors in the spinal cord and that glycine may be involved in this inhibition.

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