Minoru Tsuji

The role of δ-opioid receptor subtypes in cocaine- and methamphetamine-induced place preferences

Abstract The effects of δ-receptor antagonists on cocaine- and methamphetamine-induced place preferences were examined in rats. Cocaine- and methamphetamine-induced place preferences were significantly attenuated by naltrindole (NTI: a non-selective δ-opioid receptor antagonist). Furthermore, naltriben (NTB: a selective δ 2 -opioid receptor antagonist), but not 7-benzylidenenaltrexone (BNTX: a selective δ 1 -opioid receptor antagonist), attenuated the cocaine- and methamphetamine-induce place preferences. These results suggest that δ-opioid receptors, particularly δ 2 -opioid receptors, may be involved in the reinforcing effects of cocaine and methamphetamine.

Differential effects of μ,δ- and κ-opioid receptor agonists on the discriminative stimulus properties of cocaine in rats

Abstract The effects of selective μ-, δ- and κ-opioid receptor agonists on the discriminative stimulus properties of cocaine were examined in rats trained to discriminate between cocaine (10 mg/kg) and saline. Cocaine produced a dose-related increase in cocaine-appropriate responses in all of the rats. In generalization tests, neither morphine (μ-opioid receptor agonist) nor N -methyl- N -7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-11-4-benzofuranacetamide (U50,488H: κ-opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. On the other hand, the newly synthesized non-peptide selective δ-opioid receptor agonist 2-methyl-4 a α-(3-hydroxyphenyl)-1,2,3,4,4 a ,5,12,12 a α-octahydro-quinolino(2,3,3,– g )isoquinoline (TAN-67) partially generalized (56.7% cocaine-appropriate responses) to the discriminative stimulus properties of cocaine. Intracerebroventricular (i.c.v.) administration of [ d -Ala 2 ]deltorphin II (peptide δ 2 -opioid receptor agonist) completely generalized, while neither [ d -Ala 2 ,MePhe 4 ,Gly-ol 5 ]enkephalin (DAMGO; μ-opioid receptor agonist) nor [ d -Pen 2 , d -Pen 5 ]enkephalin (DPDPE; δ 1 -opioid receptor agonist) generalized to the discriminative stimulus properties of cocaine. These results suggest that the discriminative stimulus properties of cocaine may be partially mediated by δ-opioid (especially δ 2 -opioid) receptors. In combination tests, pretreatment with morphine (3.0 mg/kg) and TAN-67 (3.0 and 10 mg/kg) significantly potentiated the discriminative stimulus properties cocaine. In contrast, pretreatment with U50,488H (2.0 and 4.0 mg/kg) scarcely shifted the discriminative stimulus properties of cocaine. Furthermore, the potentiating effect of 3.0 mg/kg morphine on the discriminative stimulus properties of cocaine was attenuated by 2.0 mg/kg U50,488H. In contrast, the potentiating effect of 10 mg/kg TAN-67 on the discriminative stimulus properties of cocaine was not reversed by either 2.0 or 4.0 mg/kg U50,488H. These results suggest that μ-, δ- and κ-opioid receptor agonists modulate the discriminative stimulus properties of cocaine through different mechanisms, perhaps through different effects on the dopaminergic system. ©xa01997 Elsevier Science B.V.

Involvement of dopamine-dependent and -independent mechanisms in the rewarding effects mediated by δ opioid receptor subtypes in mice

The rewarding effects of the delta 1 opioid receptor agonist [D-Pen2, Pen5]enkephalin (DPDPE) and the delta 2 opioid receptor agonist [D-Ala2]deltorphin II (DELT) on the activity of mesolimbic and nigrostriatal dopamine (DA) neurons were examined in mice. Both DPDPE (15 nmol, i.c.v.) and DELT (5 nmol, i.c.v.) produced a significant place preference in mice. The DPDPE (15 mol, i.c.v.)-induced place preference was abolished by 7-benzylidenenaltrexone (BNTX; 0.5 mg/kg, s.c.), a delta1 opioid receptor antagonist, but not by naltriben (NTB; 0.5 mg/kg, s.c.), a delta 2 opioid receptor antagonist. In contrast, the DELT (5 nmol, i.c.v.)-induced place preference was antagonized by NTB, but not BNTX. I.c.v.. injection of DPDPE, but not DELT, at a dose that produced a significant place preference produced a significant elevation of DA turnover in the mouse limbic forebrain, and this effect of DPDPE was antagonized by BNTX but not by NTB. In addition, i.c.v. injection of DPDPE or DELT not affect DA turnover in the mouse striatum. These results suggest that the rewarding effects produced by the activation of central delta 1, but not delta 2, opioid receptors may be caused through the enhancement of the mesolimbic DA neurotransmission, and confirm our previous hypothesis that the DA-dependent and -independent mechanisms may exist in the rewarding effects produced by the activation of central delta opioid receptor subtypes.

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

The effects of a potent 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-Pen2, Pen5]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-Ala2]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 ED50 value of morphine decreased. These effects 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.

Involvement of GABAB receptor systems in experimental depression: baclofen but not bicuculline exacerbates helplessness in rats.

There are two gamma-aminobutyric acid (GABA) hypotheses of the antidepressants action: an increase in GABAA neurotransmission or a decrease in GABAB neurotransmission may contribute to action of antidepressants. In this study, involvement of GABAA and GABAB receptor systems was examined in the learned helplessness paradigm in rats. Rats were injected with bicuculline or baclofen for 14 days. On day 14, the rats were subjected to 15 inescapable shocks. On day 15, they underwent the 40-trial escape test. Baclofen exacerbated the escape failures in the rats subjected to the inescapable shocks, although baclofen had no effects in the animals without shock pre-treatment. Bicuculline failed to influence the escape failures in the rats with the 15-shock pre-treatment. These results suggest that the long-term increase in GABAB neurotransmission but not the long-term attenuation of GABAA neurotransmission may be related to helplessness in rats.

Involvement of GABAB receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats

Involvement of GABAergic systems in action of antidepressants was examined in the learned helplessness paradigm in rats. Rats were treated with desipramine, baclofen or muscimol for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks induced the subsequent increase in escape failures in the escape test. Desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of desipramine, although baclofen had no effects on the increased escape failures when it was injected alone. Muscimol at any dose failed to influence the increased escape failures. Therefore, it is suggested that the long-term decrease in GABAB neurotransmission may be involved in the action of antidepressants. Our present results do not support the hypothesis that activation of GABAA receptors may contribute to the action of antidepressants.

Involvement of δ1 and δ2 Opioid Receptor Subtypes in the Development of Physical Dependence on Morphine in Mice

The effects of the highly selective δ opioid receptor antagonists naltrindole (NTI) for δ1 and δ2 naltriben (NTB) and naltrindole 5′-isothiocyanate (5′-NTII) for δ2 and 7-benzylidenenaltrexone (BNTX) for δ1 on the development of physical dependence on morphine were investigated in mice. Neither NTI (3 mg/kg, sc), NTB (0.5 mg/kg, sc), 5′-NTII (0.5 mg/kg, sc) nor BNTX (0.5 mg/kg, sc) suppressed the antinociception induced by morphine (10 mg/kg, sc). Pretreatment with NTI (3 mg/kg, sc), NTB (0.5, 1.0 mg/kg, sc) or 5′-NTII (0.5, 1.0 mg/kg, sc) during chronic treatment with morphine for 5 days significantly suppressed naloxone-induced body-weight loss in morphine-dependent mice. The incidence of jumping and body shakes in morphine-dependent mice that were pretreated with NTI, NTB or 5′-NTII were significantly lower than with morphine alone. Pretreatment with BNTX (0.5, 1.0 mg/kg, sc) during chronic treatment with morphine also significantly suppressed naloxone-induced body-weight loss in morphine-dependent mice, but this suppression was weaker than that by the antagonists. In contrast to mice that had been pretreated with NTI, NTB or 5′-NTII, the incidence of several withdrawal signs, such as jumping and body shakes, was not significantly affected in morphine-dependent mice that were pretreated with BNTX. These findings suggest that both δ2 and δ1 opioid receptors may play important roles in modulating the development of physical dependence on morphine.

Antisense oligodeoxynucleotide to δ opioid receptors attenuates morphine dependence in mice

Abstract The effect of intracerebroventricular (i.c.v.) treatment with antisense oligodeoxynucleotide (A-oligo) to δ opioid receptor mRNA on the morphine-induced place preference and naloxone-precipitated jumping was examined in morphine-dependent mice. Morphine (5 mg/kg, s.c.) produced a significant place preference. I.c.v. pretreatment with A-oligo (0.01–1 μg/mouse) dose-dependently attenuated this morphine (5 mg/kg, s.c.)-induced place preference, while mismatched oligodeoxynucleotide (M-oligo; 1 μg/mouse, i.c.v.) was ineffective. Naloxone (3 mg/kg, s.c.) precipitated jumping in morphine-dependent mice. I.c.v. pretreatment with A-oligo (1 μg/mouse) attenuated this naloxone (3 mg/kg, s.c.)-precipitated jumping in morphine-dependent mice, while M-oligo (1 μg/mouse, i.c.v.) was ineffective. These data demonstrate that the selective reduction in supraspinal δ opioid receptor function caused by pretreatment with A-oligo attenuated the morphine-induced place preference and naloxone-precipitated jumping in morphine-dependent mice, suggesting that the rewarding effect of and physical dependence on morphine may be modulated by central δ opioid receptors.

The effects of dopamine D1 and D2 receptor antagonists on the rewarding effects of δ1 and δ2 opioid receptor agonists in mice

The effects of the dopamin D1 antagonist SCH23390 and the D2 antagonist sulpiride on the rewarding effects of δ opioid receptor agonists were examined in mice. Both [d-Pen2, Pen5]enkephalin (DPDPE, 1–15 nmol, ICV), a selective δ1 opioid receptor agonist, and [d-Ala2]deltorphin II (DELT, 0.5–5 nmol, ICV), a selective δ2 opioid receptor agonist, produced a dose-dependent place preference in mice. The DPDPE (15 nmol, ICV)-induced place preference was abolished by BNTX (0.5 mg/kg, SC), a δ1 opioid receptor antagonist, but not by NTB (0.5 mg/kg, SC), a δ2 opioid receptor antagonist. In contrast, the DELT (5 nmol, ICV)-induced place preference was antagonized by NTB, but not BNTX. Pretreatment with SCH23390 (3 µg/kg, SC) abolished the DPDPE-induced place preference, but not affect the DELT-induced place preference. Moreover, pretreatment with sulpiride (40 mg/kg, SC) did not modify the place preference induced by DPDPE or DELT. In the present study, we found that the activation of both central δ1 and δ2 opioid receptors produced rewarding effects. Furthermore, these results suggest that the rewarding effects of δ1 opioid receptor agonist may be produced through activation of the central dopaminergic system, especially dopamine D1 receptors, whereas the rewarding effects of δ2 opioid receptor agonists may be produced by some other mechanism(s).

Effect of naltrindole on the development of physical dependence on morphine in mice: A behavioral and biochemical study

The effect of pretreatment with a delta opioid receptor antagonist, naltrindole (NTI), on the development of physical dependence on morphine was investigated in mice. Several withdrawal signs, an increase in cortical noradrenaline (NA) turnover and a decrease in dopamine (DA) turnover in the limbic forebrain were observed following naloxone challenge in morphine-dependent mice. Pretreatment with NTI (0.3-5 mg/kg, s.c.) during chronic morphine treatment dose-dependently suppressed the behavioral and biochemical changes after withdrawal. The blocking effects of NTI suggest that delta opioid receptors may play a significant role in modulating the development of physical dependence on morphine.