Modification of morphine-induced place preference by diabetes

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Abstract

The effects of diabetes on morphine-induced place preference in mice were examined. Morphine caused dose-related place preference in both diabetic and non-diabetic mice. This morphine-induced place preference in diabetic mice was greater than that in non-diabetic mice. The morphine (5 mg/kg)-induced place preference in both diabetic and non-diabetic mice was significantly antagonized by pretreatment with β-funaltrexamine, a selective μ-opioid receptor antagonist, but not with naloxonazine, a selective μ1-opioid receptor antagonist. The morphine (5 mg/kg)-induced place preference in non-diabetic mice was attenuated by pretreatment with either naltriben, a selective δ2-opioid receptor antagonist, or 7-benzylidenenaltrexone, a selective δ1-opioid receptor antagonist. Moreover, the morphine (10 mg/kg)-induced place preference in non-diabetic mice was antagonized by pretreatment with 7-benzylidenenaltrexone (0.7 mg/kg). Although 7-benzylidenenaltrexone had no effect on the place preference induced by 5 mg/kg morphine in diabetic mice, it reduced the place preference induced by 3 mg/kg morphine. Furthermore, the morphine (5 mg/kg)-induced place preference in diabetic mice was significantly antagonized by co-pretreatment with β-funaltrexamine (10 mg/kg) and 7-benzylidenenaltrexone (0.7 mg/kg). 2-Methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino[2,3,3-g]isoquinoline (TAN-67), a non-peptide δ-opioid receptor agonist, produced place preference in diabetic, but not in non-diabetic mice. These results support the hypothesis that the morphine-induced place preference is mainly mediated through the activation of the μ2-opioid receptor. Furthermore, the enhancement of the morphine-induced place preference in diabetic mice may be due to the up-regulation of δ-opioid receptor-mediated functions.

Introduction

The reinforcing effects of opioids, such as morphine and heroin, have been demonstrated by using self-administration and conditioned place preference procedures in rodents and other mammals. Place conditioning studies with rats and mice have provided evidence that the motivational effects of μ- and δ-opioid agonists result from the activation of μ- and δ-opioid receptors in central neuron systems, respectively (Shippenberg et al., 1987; Suzuki et al., 1991, Suzuki et al., 1993, Suzuki et al., 1994). These findings suggest that the activation of supraspinal μ- and/or δ-opioid receptors is required for the expression of the reinforcing effect of opioids. We previously demonstrated that systemically administered morphine produce place preference in μ1-opioid receptor-deficient CXBK mice (Suzuki et al., 1993). Furthermore, the morphine-induced place preference in mice was not blocked by pretreatment with naloxonazine, a selective μ1-opioid receptor antagonist. Based on these results, we suggested that morphine produces its motivational effects via naloxonazine-insensitive μ-opioid receptors, namely μ2-opioid receptors (Suzuki et al., 1993). Furthermore, we suggested that δ1- and δ2-opioid receptors may be involved in the modulation of the reinforcing effect of morphine, since morphine-induced place preference was blocked by pretreatment with naltrindole, a selective δ-opioid receptor antagonist, 7-benzylidenenaltrexone, a selective δ1-opioid receptor antagonist, and naltriben, a selective δ2-opioid receptor antagonist (Suzuki et al., 1994).

It has been reported that the antinociceptive potency, but not maximal effect, of morphine is decreased in several rodent models of hyperglycemia, including a spontaneously diabetic strain of mice and streptozotocin-induced diabetes, a model of type I diabetes (Simon and Dewey, 1981). The induction of physical dependence on morphine was also significantly decreased in streptozotocin-induced diabetic mice and genetically diabetic mice (Shook and Dewey, 1986; Kamei et al., 1995a). In a clinical study, Morley et al. (1984)showed a significantly decreased pain tolerance in diabetic patients and in normal fasted subjects and suggested that the painful neuropathy experienced by some diabetic patients might involve an interaction of glucose with the action of endogenous opioid peptides.

Recently, we demonstrated that the potency of the naloxonazine-sensitive pharmacological actions of μ-opioid receptor agonists, i.e., supraspinal antinociception, Straub tail reaction and locomotor-enhancing effect, in diabetic mice were markedly reduced as compared with those in non-diabetic mice (Kamei et al., 1994a, Kamei et al., 1994c, Kamei et al., 1995a). Furthermore, we reported that μ1-opioid receptor-mediated naloxone-precipitated signs of withdrawal from physical dependence on morphine in diabetic mice are significantly less than those in non-diabetic mice (Kamei et al., 1995a). In contrast, there was no significant difference in the naloxonazine-insensitive pharmacological actions of an μ-opioid receptor agonist, i.e., spinal antinociception, antitussive effect and gastrointestinal antitransit effect, between diabetic mice and non-diabetic mice (Kamei et al., 1993a, Kamei et al., 1993b, Kamei et al., 1994a, Kamei et al., 1995b). Therefore, we proposed that mice with diabetes are selectively hyporesponsive to activation of μ1-opioid receptors, but are normally responsive to μ2-opioid receptors. However, we previously reported that the 7-benzylidenenaltrexone-sensitive antinociceptive effect of [d-Pen2,5]enkephalin (DPDPE) was significantly greater in diabetic mice than in non-diabetic mice, whereas there was no significant difference in the naltriben-sensitive antinociceptive effect of [d-Ala2]deltorphineII between diabetic and non-diabetic mice (Kamei et al., 1994b). These findings suggested that mice with diabetes are selectively hyperresponsive to activation of δ1-opioid receptors, but are normally responsive to δ2-opioid receptors. Therefore, functional abnormalities in μ- and δ-opioid receptor functions of diabetic animals may alter the reinforcing effect of morphine.

Thus, the primary aim of our study was to compare morphine-induced place preference in diabetic and non-diabetic mice to clarify our hypothesis that functional abnormalities in μ- and δ-opioid receptor functions of diabetic animals may alter the reinforcing effect of morphine.

Section snippets

Animals

Male ICR mice (Tokyo Laboratory Animals Science, Tokyo, Japan), weighing about 20 g at the beginning of the experiments, were used. They had free access to food and water in an animal room which was maintained at 22±1°C with a 12 h light–dark cycle. Animals were rendered diabetic by an injection of streptozotocin (200 mg/kg, i.v.) prepared in 0.1 N citrate buffer at pH 4.5. Age-matched non-diabetic mice were injected with vehicle alone. The experiments were conducted 2 weeks after injection of

Effects of diabetes on morphine-induced place preference

As shown in Fig. 1, none of the mice receiving saline in conditioning sessions exhibited a significant preference for either compartment of the test box. Testing of saline-treated mice in the test session revealed that neither non-diabetic nor diabetic mice showed a significant preference for one side of the test box over the other. The place conditioning produced by morphine is shown in Fig. 1. In non-diabetic mice, morphine, over a dose range from 3 to 30 mg/kg, s.c., caused a dose-related

Discussion

The present study demonstrated that morphine produced dose-related conditioned place preference in both diabetic and non-diabetic mice. Furthermore, the morphine-induced place preference was significantly antagonized by pretreatment with β-funaltrexamine, a selective μ-opioid receptor antagonist, but not naloxonazine, a selective μ1-opioid receptor antagonist, in both diabetic and non-diabetic mice. Similarly, Suzuki et al. (1993)demonstrated that morphine-induced place preference was not

Acknowledgements

We thank Ms. N. Katoh and Ms. Y. Maki for their technical assistance.

References (37)

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