Effect of the highly selective and nonpeptide delta opioid receptor agonist TAN-67 on the morphine-induced place preference in mice

The effect of 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12a alpha-octahydroquinolino [2,3,3,-g]isoquinoline (TAN-67), a selective non-peptide delta opioid receptor agonist, on the morphine-induced place preference was examined in mice. Morphine (1-5 mg/kg, s.c.) produced a dose-related place preference in mice. In contrast, administration of TAN-67 (5-20 mg/kg, s.c.) did not result in a preference for either the drug- or vehicle-associated place. When TAN-67 (5-20 mg/kg, s.c.) was coadministered with morphine (1 mg/kg, s.c.), the morphine-induced place preference was enhanced dose dependently, and this effect of TAN-67 was suppressed by the pretreatment with naltrindole (1 mg/kg, s.c.), a nonselective delta opioid receptor antagonist, 7-benzylidenenaltrexone (0.05 and 0.5 mg/kg, s.c.), a selective delta 1 opioid receptor antagonist, and naltriben (0.05 and 0.5 mg/kg, s.c.), a selective delta 2 opioid receptor antagonist. In biochemical study, morphine (1 mg/kg, s.c.) or TAN-67 (20 mg/kg, s.c.) alone did not modify dopamine turnover in the limbic forebrain. Coadministration of TAN-67 (20 mg/kg, s.c.) with morphine (1 mg/kg, s.c.) increased DA turnover in the limbic forebrain. This increase in DA turnover in the limbic forebrain was suppressed by pretreatment with naltrindole (1 mg/kg, s.c.) or 7-benzylidenenaltrexone (0.5 mg/kg, s.c.), but not by naltriben (0.5 mg/kg, s.c.). Our results demonstrate that coadministration of TAN-67 with morphine enhances the morphine-induced place preference via activation of both delta 1 and delta 2 opioid receptors, suggesting that both delta 1 and delta 2 opioid receptors may modulate the morphine-induced rewarding effect. In addition, we also found that although both delta 1 and delta 2 opioid receptors may be implicated in the modulation of rewarding effect of morphine, the mechanisms involved may be different for each receptor subtypes, i.e., mu-delta 1 interaction may mainly modulate the rewarding effect of morphine by enhancing neurotransmission of mesolimbic dopamine neurons, although modulation by mu-delta 2 opioid receptor interaction may involve some other dopamine-independent mechanisms.