Disseleneto de m-trifluormetil-difenila modula as adaptações neurotóxicas e comportamentais induzidas pela retirada da morfina em camundongos

Abstract

Repeated use of morphine is controversial because it leads to the development of withdrawal syndrome, phenomenon involving a number of neuronal adaptations, which results on manifestations of physical signs and a state affective aversive. On the other hand, although the antidepressant-like effect exerted by m-trifluoromethyl-diphenyl diselenide (m-CF3PhSe)2 has been related to modulation of opioid receptors in animal models, repeated administration of this compound did not induce any characteristic undesirable effects of μ receptor agonists, characterized by tolerance and physical withdrawal signs. Furthermore, it has been shown that (m-CF3PhSe)2 prevented the neuroadaptations and the re-conditioning signs in rats exposed to amphetamine. In this context, the present study investigated the effect of (m-CF3PhSe)2 on the physical signs and on the depressive-like phenotype during morphine withdrawal, as well as the neuroadaptive processes involved in hippocampus of mice. The study was carried out using adult male Swiss mice (CEUA nº. 8756060317). In the first six days, the animals received escalating doses of morphine (20 – 100 mg/kg), twice a day, by the subcutaneous route. From the seventh day, the animals were treated with (m-CF3PhSe)2 at different doses (5 and 10 mg/kg), once a day intragastrically, over the next three days whereas morphine injections were discontinued to induce the spontaneous withdrawal syndrome. On the ninth day of the experimental protocol, 30 min after the last administration of (m-CF3PhSe)2, the animals performed the behavioral tests to assess the physical signs of withdrawal and the depressive-like phenotype on the tail suspension test and the forced swim test, respectively. After, the samples of hippocampus were collected for ex vivo analyses, including oxidative stress markers, protein levels related to antioxidant defenses, NMDA receptor subunits (2A and 2B) and the signaling pathways of the proBDNF and the mBDNF. The results demonstrated that hippocampal neuroadaptations mediated by the redox imbalance, the decrease on NMDA receptors levels and the stimulation of proBDNF/p75NTR/JNK pro-apoptotic pathway without affecting mBDNF/TrkB/ERK/CREB neurotrophic signaling, may contribute to the development of physical signs and the depressive-like phenotype in morphine withdrawn-mice. In contrast, (m-CF3PhSe)2 treatment in both doses reversed the behavioral adaptations induced during morphine withdrawal in mice; however, the highest dose of this compound intensified one of the parameters related to physical withdrawal signs. Besides (m-CF3PhSe)2 reestablished the balance in redox signaling and in synaptic plasticity by inhibiting proBDNF signaling without altering that of mBDNF as well as restored the levels of NMDA receptor in hippocampus of morphine withdrawn-mice. In conclusion, the present study demonstrated that the neuroprotective effects of (m-CF3PhSe)2, mediated primarily by its antioxidant property, modulated the hippocampal neurotoxic events and, thus, attenuated the manifestation of physical signs and depressive-like phenotype in morphine withdrawn-mice.