To clarify the pharmacological properties of (+)2-Methyl-4aalpha-(3-hydroxyphenyl)-1, 2, 3, 4, 4a, 5, 12, 12aalpha-octahydro-quinolino[2, 3, 3-g]
isoquinoline ((+)-
TAN-67), the effect of (+)-
TAN-67 on the antinociception induced by the intrathecal (i.t.) administration of
nociceptin/orphanin FQ was studied in mice using the tail-flick test and the
formalin test. I.t. administration of (+)-
TAN-67, at doses of 1 to 10 ng, facilitated the tail-flick response in a dose-dependent manner in mice. In addition, i.t. administration of (+)-
TAN-67 (1 to 10 ng) in mice produced a marked
pain-like aversive responses. I.t. pretreatment with D-Pro(9)-[spiro-gamma-
lactam]-Leu(10)-Trp(11)-
physalaemin(1-11) (GR82334, 0.1-1.0 nmol), a potent and selective
tachykinin NK(1) receptor antagonist, dose-dependently blocked the reduction of the tail-flick response induced by (+)-
TAN-67. Furthermore, (+)-
TAN-67-induced facilitation of the tail-flick response was abolished in
capsaicin-treated mice. On the other hand, (+)-
TAN-67-induced flinching responses were dose-dependently and significantly reduced by i.t. pretreatment with GR82334 (0.1-1.0 nmol). The duration of i.t. (+)-
TAN-67-induced flinching responses was significantly reduced in
capsaicin-treated mice as compared with naive mice. I.t. administration of
nociceptin/orphanin FQ (1-10 nmol) dose-dependently increased the tail-flick latency. I.t. administration of
nociceptin/orphanin FQ (0.1-1.0 nmol) significantly and dose-dependently reduced the first-phase nociceptive response, but not the second-phase nociceptive response. I.t. pretreatment with (+)-
TAN-67 (0.3-3.0 microg) for 30 min dose-dependently attenuated the antinociception induced by i.t.
nociceptin (10 nmol) in the tail-flick test. Furthermore, the antinociceptive effect of
nociceptin/orphanin FQ (1 nmol, i.t.) on the first-phase response in the
formalin test was dose-dependently attenuated by s.c. pretreatment with (+)-
TAN-67 (0.3-3.0 microg). (+)-
TAN-67 (0.3-3.0 microg, i.t.), by itself, did not facilitate the tail-flick response or produce apparent behavioral changes. It is possible that (+)-
TAN-67 has an antagonistic effect on
nociceptin/orphanin FQ-induced antinociception.