At the spinal level,
nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of
pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/
OFQ receptor. In the present study, we examined the involvement of the Noc/
OFQ receptor in
pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)
benzamide monohydrochloride (JTC-801).
Allodynia and
hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of
JTC-801 with IC(50) values of 32.2 and 363 pg, respectively.
JTC-801 did not induce
allodynia by itself.
Subcutaneous injection of
formalin into a hindpaw evoked biphasic
pain behaviors such as flinching and biting in mice. Noc/OFQ
at 10 pg increased the second-phase
pain behaviors evoked by 1%
formalin, whereas it strongly inhibited both the first-phase and second-phase
pain evoked by 2%
formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by
JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by
JTC-801. Furthermore, both phases of 2%
formalin-induced
pain behaviors were relieved by
JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/
OFQ receptor in the spinal cord and that
JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/
OFQ receptor under physiological and pathophysiological conditions including
pain.