The adenosinergic system is involved in sensitization to morphine withdrawal signs in rats—neurochemical and molecular basis in dopaminergic system

Abstract

RationaleExperimental data informs that not only do the dose and time duration of dependent drugs affect the severity of withdrawal episodes. Previous withdrawal experiences may intensify this process, which is referred as sensitization to withdrawal signs. Adenosine and dopamine (DA) receptors may be involved in this sensitization.ObjectivesRats were continuously and sporadically treated with increasing doses of morphine for 8 days. In rats, sporadically treated with morphine, morphine administration was modified by adding three morphine-free periods. Adenosine agonists were given during each of the morphine-free periods (six injections in total). On the 9th day, morphine was injected. One hour later, naloxone was administered to induce morphine withdrawal signs. Then, the animals were placed into cylinders and the number of jumpings was recorded. Next, the rats were decapitated and brain and brain structures (striatum, hippocampus, and prefrontal cortex) were dissected for neurochemical, molecular, and immunohistochemical experiments within DAergic pathways.ResultsWe demonstrated that previous experiences of opioid withdrawal intensified subsequent withdrawal signs. Adenosine ligands attenuated the sensitization to withdrawal signs. In a neurochemical study, the release of DA and its metabolites was impaired in all structures. Significant alterations were also observed in mRNA and protein expression of DA receptors.ConclusionsResults demonstrate that intermittent treatment with morphine induces alterations in the DAergic system which may be responsible for sensitization to morphine withdrawal signs. Although adenosine ligands attenuate this type of sensitization, they are not able to fully restore the physiological brain status.

Fluoride Affects Dopamine Metabolism and Causes Changes in the Expression of Dopamine Receptors (D1R and D2R) in Chosen Brain Structures of Morphine-Dependent Rats

“…Statistical changes in the level of 3-MT, which is formed by degradation of dopamine by COMT, were observed only in the hippocampus of morphine-withdrawal rats. This effect was similar to our previous study [26] in which characteristic and significant increases in the hippocampal 3-MT level during naloxone-induced morphine withdrawal were also measured. There is a hypothesis that in some circumstances, 3-MT may act as a neuromodulator in CNS [29] and it may be an important factor of neuro-adaptive mechanisms [30].…”

“…The dopamine level in other structures in the brain during morphine withdrawal has not been precisely defined yet. For example, in our previous results [26] and those by other authors [27], no changes in the dopamine level in the hippocampus were observed. On the other hand, in the prefrontal cortex, an increase in the dopamine level was observed during morphine withdrawal [26,28].…”

“…For example, in our previous results [26] and those by other authors [27], no changes in the dopamine level in the hippocampus were observed. On the other hand, in the prefrontal cortex, an increase in the dopamine level was observed during morphine withdrawal [26,28]. Thus, the obtained hippocampal, prefrontal, and cerebellar results confirmed the involvement of dopaminergic mechanisms during morphine withdrawal, but the precise interactions need further studies.…”

SB-334867 (an Orexin-1 Receptor Antagonist) Effects on Morphine-Induced Sensitization in Mice—a View on Receptor Mechanisms

“…An increased dopamine neurotransmission was observed during sensitization development [ 12 ]. In opioid-induced behavioral sensitization, the influence of various neurotransmitters and neuromodulators was experimentally demonstrated, including dopamine [ 12 ], glutamate [ 9 ], serotonin [ 13 , 14 ], adenosine [ 15 , 16 ], nitric oxide [ 17 ], and others. Although the mechanisms of behavioral sensitization have often been evaluated, no effective pharmacological treatment options have thus far been identified to be able to reduce that phenomenon.…”

“…The objectives of those experiments included the relationships, observed in mesolimbic brain areas in result of sporadic SB-334867 administration in morphine-sensitized mice. In our investigations, we concentrated on the expression of dopamine receptors because of the crucial role of dopamine in behavioral sensitization [ 9 , 12 , 16 , 42 ]. We also intended to recognize the expression type of both orexin receptors in the studied sensitization.…”