Adenosine A2 receptors inhibit morphine self-administration in rats

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Abstract

In the present study, the effect of adenosine receptor agonists and antagonists on morphine self-administration was investigated. Intravenous administration of morphine (0.3–3 mg/kg/injection) induced dose-dependent self-administration. The adenosine receptor antagonists, theophylline (2.5, 5, 10 mg/kg) and 3,7-Dimethyl-1-propargylxanthine (DMPX; 0.25, 0.5, 1 mg/kg), when injected 1 h before the start of the test, reduced the number of self-administered morphine infusions. The adenosine receptor antagonists when administered in the training period (11 days) greatly increased the number of morphine infusions, however, they did not induce any response by themselves. 5′-N-ethylcarboxamido-adenosine (NECA; 0.5, 1 mg/kg) and 4-[2-[[6-Amino-9-(N-ethyl-β-d-ribofuranuronamidosyl)-9H-purin-2-yl]amino] ethyl]benzenepropanoic acid (CGS21680; 0.001, 0.01, 0.025, 0.05 mg/kg), given 1 h before the start of the test, increased morphine self-administration. Although the adenosine agonists, when injected during training period (11 days), reduced morphine self-administration. Furthermore, NECA, but not CGS21680, induced significant self-administration. The adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA; 0.01, 0.1, 0.25, 0.5 and 1 mg/kg), and the adenosine A1 receptor antagonist, 8-phenyletheophylline (2, 4, 6, 8 mg/kg), themselves neither altered morphine infusion nor induced any response. These results indicate a role for adenosine A2 receptors in the expression and/or development of morphine self-administration.

Introduction

Adenosine is an important neuromodulator in the central nervous system (CNS) (Dunwiddie, 1985). Specific receptor sites for adenosine have been demonstrated within the areas of the CNS (Lee and Reddington, 1986). A great number of research findings indicate that adenosine receptors have a role in mediating opiate effects (Kaplan and Sears, 1996). Acute morphine treatment enhances the central release of adenosine, and opiate antagonist inhibits this release (Phillis et al., 1979). Adenosine receptor agonist treatment may alter (Zarrindast and Nikfar, 1994), or even potentiate morphine antinociception in animal models (Contreras et al., 1990) and in humans (Segerdhal et al., 1994). There are several studies that demonstrate that adenosine receptor agonists and antagonists influence the development of opiate tolerance and withdrawal. Some adenosine receptor agonists inhibit the development of tolerance to opiate analgesia Ahlijanian and Takemori, 1985, Germany et al., 1990, and expression of opiate withdrawal Tucker et al., 1984, Dionyssopoulos et al., 1992. The adenosine system has also been implicated in conditioned place preference (Zarrindast and Moghadamnia, 1997), however, there is little evidence for possible effects of the adenosine system on morphine self-administration. In this study the influence of some adenosine receptor agonists and antagonists on morphine self-administration was investigated.

Section snippets

Animals

Male Sprague–Dawley rats (Pasture Institute, Tehran, Iran), weighing 270–320 g at the beginning of the study were used in these experiments. The animals were housed in groups of 5–6 in plastic cages, allowed free access to food and water and maintained on a 12-h light–dark cycle (lights on 1900–0700) and constant temperature (22±2°C). Eight animals were used in each experiment. Each animal was used only once.

Surgical procedure

The surgical procedure was based on the work described by Van Ree et al. (1978). Each

Self-administration behavior with morphine and adenosine receptor agonists and antagonists

Fig. 1 shows the self-administration induced by morphine, NECA, CGS21680, theophylline and DMPX. When rats were given the opportunity to self-administer, the number of saline self-administrations was 1–3 injections, after a period of training (a unit volume of 0.1 ml=one injection). In contrast, the animals which were given the opportunity to self-administer different doses of morphine (0.3–3 mg/kg/injection) in a period of 2 h, achieved self-administration in a dose-dependent manner. The

Discussion

The effect of the adenosine system on morphine self-administration has not been studied earlier. Many studies have described a role for adenosine and adenosine receptors in mediating opiate dependence Ahlijanian and Takemori, 1985, Ahlijanian and Takemori, 1986, Kaplan and Sears, 1996. The present study concerned the effects of adenosine agents on morphine self-administration. The results indicated that adenosine receptor agonists and antagonists both alter morphine self-administration,

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