Polysialic Acid is a α2-8-linked sialic acid chain present on cell surfaces in embryonic brains. In adult brains, polysialic acid is only observed in restricted areas where neural plasticity remodeling of neural connections or neural generation is required. Changes in polysialylation pattern are reported to be associated with immune defense and inflammation in the CNS. Opioids such as Morphine-3-Glucuronide (M3G) (a metabolite of morphine) activates neuroinflammation in a manner parallel to Lipopolysaccharide (LPS), compromising opioid-induced analgesia, and the hypothesis of this study is that M3G may affect the polysialic acid expression in neurons. The effects of M3G on the expression of polysialic acid in neurons were studied using immunocytochemistry and HPLC analysis. It was found that polysialic acid expression was significantly increased following M3G stimulation in neurons similar to LPS when compared to control cells. Polysialic acid was extracted from stimulated cell proteins by endo-neuraminidase digestion and was quantitated using DMB-labeling followed by HPLC analysis. The increased expression of Polysialic acid in M3G-stimulated neurons was validated by western blot analysis. Morphine is known to create neuroinflammation in the CNS. In adults, re-expression of Polysialic acid can be interpreted as an attempt to achieve regeneration. Therefore, upregulation of Polysialic acid in neurons following M3G stimulation may indicate cell recovery from toxic insult