Modulação dopaminérgica e glutamatérgica na recaída por morfina em ratos: influência da dieta e de fármacos nanoparticulados

Abstract

Morphine, in addition to being an analgesic drug, also has a high additive potential related to neuroadaptations of the dopaminergic and glutamatergic pathways, in addition to the increase in oxidative events in the mesocorticolimbic area, which characterizes drug addiction. The treatments available for this pathology have limitations, as they act only in drug withdrawal, without preventing relapse. Neural functions can be modified by dietary constituents, especially by the type of fatty acid (FA) consumed, the influence of supplementation of fats present in the Mediterranean diet (MD, rich in omega-3) and in Western diets (WDs: palm oil -PO and interesterified fat-IF) on the additive properties of morphine was evaluated. Male rats were submitted to the Conditioned Place Preference (CPP) protocol with morphine (4mg/Kg, i.p.), followed by behavioral assessments of preference, abstinence and drug relapse and subsequent euthanasia for molecular analysis. The consumption of WDs increased parameters of anxiety per se, locomotor sensitization and drug relapse, which was not observed with MD. At the molecular level, the WDs increased the immunoreactivity of the glucocorticoid receptor in the frontal cortex, of the dopamine transporter (DAT) and type 2 dopaminergic receptor (D2R) in the nucleus accumbens (NAc), reducing the immunoreactivity of D1R in the same area. Based on this evidence, it is important to emphasize that the consumption of WDs facilitates morphine reinstatement, which can make opioid detoxification more difficult. It is known that the chronic use of opioids can modify the glutamatergic neurotransmission as well as the hedonia evoked by the increased release of dopamine, favoring the generation of oxidative damage. These data led to the development of two subsequent protocols: evaluation of the glutamatergic antagonist topiramate in its free (S-TPM, 0.5mg/Kg, ip) and nanoescapsulated (TPM-CS-NP, 0.57mg/Kg, ip), and evaluation of the antioxidant ferulic acid, in its free form (F-FA, 0.5mg/Kg, po) and nanoencapsulated (FA-Nc, 0.5mg/Kg, po), against morphine reinstatement. Treatments with TPM-CS-NP and FA-Nc prevented drug relapse, preserving memory, which was impaired by morphine and S-TPM. In the TPM protocol, morphine increased the immunoreactivity of D1R, D2R, D3R, DAT, GluA1 and MOR in NAc and of D1R, DAT, GluA1 and MOR in the dorsal hippocampus, while TPM-CS-NP decreased the levels of D1R, D3R and GluA1 and increased DAT in NAc, decreased GluA1 and increased D2 and DAT in dorsal hippocampus, preventing drug relapse and protecting memory, which indicates the therapeutic superiority of this nanoformulation. In the FA protocol, morphine increased the levels of D1R, D3R, DAT, ΔFosB in the NAc, while the FA-Nc decreased D1R, D3R and ΔFosB and increased D2R, DAT and NRF2 in the NAc, preventing relapse to the drug, indicating a neuroprotective role of this nanoformulation. Morphine drug addiction is multifactorial and can be avoided through a consumption of MD, as well as prevented through treatments with nanoparticles of TPM and FA during abstinence.