Abstract
The present study focused upon the role of SB-334867, an orexin-1 receptor antagonist, in the acquisition of morphine-induced sensitization to locomotor activity in mice. Behavioral sensitization is an enhanced systemic reaction to the same dose of an addictive substance, which assumingly increases both the desire for the drug and the risk of relapse to addiction. Morphine-induced sensitization in mice was achieved by sporadic doses (five injections every 3 days) of morphine (10 mg/kg, i.p.), while a challenge dose of morphine (10 mg/kg) was injected 7 days later. In order to assess the impact of orexin system blockade on the acquisition of sensitization, SB-334867 was administered before each morphine injection, except the morphine challenge dose. The locomotor activity test was performed on each day of morphine administration. Brain structures (striatum, hippocampus, and prefrontal cortex) were collected after behavioral tests for molecular experiments in which mRNA expression of orexin, dopamine, and adenosine receptors was explored by the qRT-PCR technique. Additionally, the mRNA expression of markers, such as GFAP and Iba-1, was also analyzed by the same technique. SB-334867 inhibited the acquisition of morphine-induced sensitization to locomotor activity of mice. Significant alterations were observed in mRNA expression of orexin, dopamine, and adenosine receptors and in the expression of GFAP and Iba-1, showing a broad range of interactions in the mesolimbic system among orexin, dopamine, adenosine, and glial cells during behavioral sensitization. Summing up, the orexin system may be an effective measure to inhibit morphine-induced behavioral sensitization.
Highlights
Morphine is a valuable drug in clinical practice for its analgesic efficacy
The presented study aimed to investigate the impact of the orexin system on the acquisition of morphine-induced behavioral sensitization
It confirmed that SB-334867, the selective antagonist of the orexin type 1 (OX-1) receptor, inhibited the acquisition of morphine-induced sensitization to the locomotor activity in mice
Summary
Morphine is a valuable drug in clinical practice for its analgesic efficacy. Its use is, limited because of addictive properties. (GABA) system, increasing dopamine release and inducing euphoria for the user [1]. It is well-known that a chronic administration of morphine leads to physical and psychological addiction [2, 3]. An intermittent administration of that drug develops behavioral sensitization, defined as an enhanced systemic reaction to the same dose of morphine or any other addictive substance [4, 5]. Behavioral sensitization is a longlasting phenomenon, associated with both context-dependent and context-independent factors which may lead to addiction relapse [6, 7]. The mechanisms, which are involved in behavioral sensitization, are not yet fully understood, an influence of the mesocorticolimbic system in that phenomenon has been repeatedly documented [7, 9]. The mechanisms of behavioral sensitization have often been evaluated, no effective pharmacological treatment options have far been identified to be able to reduce that phenomenon
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