The modulatory effect of (+)-TAN-67 on the antinociceptive effects of the nociceptin/orphanin FQ in mice

Abstract

To clarify the pharmacological properties of (+)2-Methyl-4 aα-(3-hydroxyphenyl)-1, 2, 3, 4, 4 a, 5, 12, 12 aα-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-γ-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 μg) 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 μg). (+)-TAN-67 (0.3–3.0 μg, 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.