Effects of a highly selective nonpeptide δ opioid receptor agonist, TAN-67, on morphine-induced antinociception in mice

Abstract

The effects of a potent and highly selective nonpeptide δ opioid receptor agonist, 2- metnyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67), on morphine-induced antinociception were examined using the warm-plate (51 °C) method. When a peptide δ 1, opioid receptor agonist, [D-Pen 2, Pen 5]enkephalin (DPDPE), was co-administered with i.c.v. morphine, low-dose morphineinduced antinociception was significantly increased. In Contrast, I.c.v. coadministration of a peptide δ 2 opioid receptor agonist, [D-Ala 2]deltorphin II (DELT), with morphine did not affect the morphine-induced antinociception. When morphine and TAN-67 were co-administered i.c.v., low-dose morphine-induced antinociception was significantly increased. Moreover, when TAN-67 and morphine were co-administered s.c., the morphine dose-response curve shifted to the left and the ED 50 value of morphine decreased. These effects of DPDPE and TAN-67 were antagonized by the δ opioid receptor antagonist naltrindole (NTI) and the δ 1, opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) not by the δ 2 opioid receptor antagonist naltriben (NTB). Moreover, the μ opioid receptor antagonist β-FNA also antagonized the effects of DPDPE and TAN-67. These results suggest that the effect of TAN-67 may result from the activation of central δ 1 opioid receptors, since the effect of TAN-67 was antagonized by NTI and BNTX, but not NTB. Furthermore, since pretreatment with β-FNA also antagonized the effects of both DPDPE and TAN-67, a β-FNA-sensitive site, i.e. a μ-δ complex site, may play an important role in the modulation of morphine-induced antinociception.