Previousfindings from our lab show a long-lasting psychostimulant-induced sensitizationphenomenon at the immune level in a manner parallel to that occurring in thelimbic and immune enkephalinergic systems (Assís et al., 2006, 2009, 2011). Wealso demonstrated that the enkephalinergic system is essential for behavioraland molecular sensitization to cocaine within the nucleus accumbens (NAc) andcaudate putamen (CPu) (Mongi-Bragato et al., 2014). However, there is nodescription so far of how microglia is involved in psychomotor sensitizationand how the enkephalinergic system participates in this. We treated maleC57B/6J mice daily with naloxone (1 mg/kg i.p.) or vehicle previous to cocaine(15 mg/kg i.p.) and vehicle for 9 days, followed by a cocaine challenge (7.5mg/kg i.p.) on day 21 of the treatment. The immunohistochemistry was performedin the areas of interest using CD11b and met-ENK antibodies. Cytokines weremeasured by qRT-PCR. In the control treatment, microglia cells had small somaand ramified processes. Repeated administration of cocaine inducedmorphological changes of microglial cells indicative of cell activation andalso increased production of pro-inflammatory cytokines such as TNF-α, which wasreversed by naloxone pretreatment. These preliminary results could be key to abetter understanding of the role of the enkephalinergic system in theimmunological signaling system in drug addiction and may provide a newtherapeutic target.