Characterization of nociceptin hyperalgesia and allodynia in conscious mice

Abstract

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.

Characterization of Nociceptin/Orphanin FQ-Induced Pain Responses by the Novel Receptor AntagonistN-(4-Amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) Benzamide Monohydrochloride

“…We previously showed that intrathecal (i.t.) administration of Noc/OFQ at very low doses (picogram range) induced allodynia, a state of discomfort and pain evoked by innocuous tactile stimuli, as well as hyperalgesia in conscious mice (Okuda-Ashitaka et al, 1996;Hara et al, 1997). On the other hand, i.t.…”

Modification of Nociception and Morphine Tolerance by the Selective Opiate Receptor-Like Orphan Receptor Antagonist (–)-cis-1-Methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111)

“…morphine (Mogil et al, 1996). At the spinal level, intrathecal injection of low concentrations of nociceptin in mice causes allodynia and hyperalgesia (Hara et al, 1997), whereas at higher concentrations this peptide can cause analgesia (King et al, 1997;Tian et al, 1997). These effects are mediated at both a presynaptic site of action in afferent nerve terminals, and at a postsynaptic site of action on spinal interneurons (Neal et al, 1999).…”

Spinorphin, an Endogenous Inhibitor of Enkephalin-Degrading Enzymes, Potentiates Leu-Enkephalin-Induced Anti-allodynic and Antinociceptive Effects in Mice

“…Hara et al showed that i.t. injection of nociceptin at 2.5 ng /kg induced the maximal allodynia in mice (27) and this dose corresponded to 50 pg /mouse (i.t.) which was used in this study.…”