Modification of morphine-induced place preference by diabetes
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)
- et al.
Conditioned place preference with morphine: The effect of extinction training on the reinforcing CR
Pharmacol. Biochem. Behav.
(1984) - et al.
Intracranial self-administration of morphine into the ventral tegmental area in rats
Life Sci.
(1981) - et al.
Morphine-induced activation of A10 dopamine neurons in the rat
Brain Res.
(1983) - et al.
Possible involvement of μ2-mediated mechanisms in μ-mediated antitussive activity in the mouse
Neurosci. Lett.
(1993) - et al.
Streptozotocin-induced diabetes selectively reduces antinociception mediated by μ1-opioid receptors, but not that mediated by μ2-opioid receptors
Neurosci. Lett.
(1994) - et al.
Streptozotocin-induced diabetes selectively enhances antinociception mediated by δ1- but not δ2-opioid receptors
Life Sci.
(1994) - et al.
Effects of diabetes on the morphine-induced Straub tail reaction in mice
Neurosci. Lett.
(1994) - et al.
Effects of diabetes on spontaneous locomotor activity in mice
Neurosci. Lett.
(1994) - et al.
Antinociceptive effects of the selective non-peptidic δ-opioid receptor agonist TAN-67 in diabetic mice
Eur. J. Pharmacol.
(1995) - et al.
Naloxonazine actions in vivo
Eur. J. Pharmacol.
(1986)
Anatomy of CNS opioid receptors
Trends Neurosci.
Reinforcing effects of morphine in the nucleus accumbens
Brain Res.
Reinforcing effects of morphine microinjection into ventral tegmental area
Pharmacol. Biochem. Behav.
Motivational properties of opioids: Evidence that activation of δ-opioid receptors mediates reinforcement processes
Brain Res.
Morphine-induced place preference in the CXBK mouse: Characteristics of μ-opioid receptor subtypes
Brain Res.
Reinforcing effects of brain microinjections of morphine revealed by conditioned place preference
Brain Res.
Morphine and nigrostiaral function in the rat and mouse: The role of nigral and striatal opiate receptors
Neuropharmacology
Opposite motivational effects of endogenous opioids in brain and periphery
Nature
Cited by (5)
Enhanced vulnerability to tobacco use in persons with diabetes: A behavioral and neurobiological framework
2016, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Also, diabetic rats do not display changes in cocaine intake (Galici et al., 2003a) but show a decrease in cocaine-induced CPP (Kamei and Ohsawa, 1997). Although diabetic rats display an increase in CPP produced by methamphetamine (Bayat and Haghparast, 2015; Kamei and Ohsawa, 1996) and morphine (Kamei et al., 1997; Samandari et al., 2013). The disparate findings in these studies are unclear despite a consistent alteration in dopamine function.
Functional effects of systemically administered agonists and antagonists of μ, δ, and κ opioid receptor subtypes on body temperature in mice
2002, Journal of Pharmacology and Experimental TherapeuticsOpioids, reward and addiction: An encounter of biology, psychology, and medicine
1999, Pharmacological Reviewsβ-Phenylethylamines and the isoquinoline alkaloids
1999, Natural Product Reports