The role of δ-opioid receptors in the discriminative stimulus properties of a low dose of methamphetamine

Abstract

The effects of selective μ-, δ- and κ-opioid receptor agonists and antagonists on the discriminative stimulus properties of methamphetamine were examined in rats that had been trained to discriminate between methamphetamine (0.4 mg/kg) and saline. Methamphetamine produced a dose-related increase in methamphetamine-appropriate responses in all of the rats. In generalization tests, neither morphine (a μ-opioid receptor agonist: 0.3–10 mg/kg) nor 3,4-dichloro- N-[2-(1-pyrrolidinyl)cyclohexo]benzeneacetamide (U50,488H: a κ-opioid receptor agonist: 1.0–8.0 mg/kg) generalized to the discriminative stimulus properties of methamphetamine. A newly synthesized non-peptide selective δ-opioid receptor agonist 2-methyl-4a α-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a α-octahydroquinolino(2,3,3,-g)isoquinoline (TAN-67: 32 mg/kg) partially generalized (70% methamphetamine-appropriate responses) to the discriminative stimulus properties of methamphetamine. In combination tests, pretreatment with the μ- and κ-opioid receptor antagonists, β-funaltrexamine (9.0 mg/kg) and nor-binaltorphimine (10 mg/kg), respectively, had little or no influence on the discriminative stimulus properties of methamphetamine. In contrast, pretreatment with naltrindole (a non-selective δ-opioid receptor antagonist: 3.0 mg/kg) or naltriben (a selective δ 2-opioid receptor antagonist: 1.0 mg/kg), but not with 7-benzylidenenaltrexone (a selective δ 1-opioid receptor antagonist: 0.5 and 1.0 mg/kg), significantly attenuated the discriminative stimulus properties of methamphetamine. However, naltrindole (3.0 mg/kg) did not significantly attenuate the discriminative stimulus properties of methamphetamine at a higher training dose (1.0 mg/kg). Our findings may have some bearing on the relative importance of the role of δ-opioid (especially δ 2-opioid) receptors in the discriminative stimulus properties of a low dose of methamphetamine.