EFFECTS OF A HIGHLY SELECTIVE NONPEPTIDE DELTA-OPIOID RECEPTOR AGONIST, TAN-67, ON MORPHINE-INDUCED ANTINOCICEPTION IN MICE

The effects of a patent and highly selective nonpeptide delta opioid receptor agonist, 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a alpha-octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67), on morphine-induced antinociception were examined using the warm-plate (51 degrees C) method. When a peptide delta(1) opioid receptor agonist, [D-Pen(2,) Pen(5)]enkephalin (DPDPE), was co-administered with i.c.v. morphine, low-dose morphine-induced antinociception was significantly increased. In contrast, i.c.v. co-administration of a peptide delta(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 delta opioid receptor antagonist naltrindole (NTI) and the delta(1) opioid receptor antagonist 7-benzylidenenaltrexone (BNTX) not by the delta(2) opioid receptor antagonist naltriben (NTB). Moreover, the mu opioid receptor antagonist beta-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 delta(1) opioid receptors, since the effect of TAN-67 was antagonized by NTI and BNTX, but not NTB. Furthermore, since pretreatment with beta-FNA also antagonized the effects of both DPDPE and TAN-67, a beta-FNA-sensitive site, i.e. a mu-delta complex site, may play an important role in the modulation of morphine-induced antinociception.