Effects of chronic inflammation and morphine tolerance on the expression of phospho-ERK 1/2 and phospho-P38 in the injured tissue.

Opioids are used in humans in the treatment of chronic osteoarticular pain, but the development of tolerance to the analgesic effects after continuous administration is still not well understood. The aim of the present study was to evaluate the expression of phospho-ERK 1/2 and phospho-p38 in mice with monoarthritis chronically exposed to morphine as a possible explanation for the development of tolerance. Inflammation was induced by intraplantar injection of complete Freund's adjuvant (CFA) and the tolerance by implantation of 75 mg morphine pellets. The results of the present study show that ERKs phosphorylation is unaltered by inflammation or morphine tolerance, each one individually, in the plantar tissue. In contrast, phospho-p38 is similarly decreased by inflammation or morphine tolerance. In naïve but not in tolerant animals, acute injection of morphine induces significant increase in phospho-p38 without any changes in phospho-ERK 1/2 expression. During inflammation, the acute injection of morphine induces a significant increase in the expression of ERK 1/2, but not in phospho-p38, in naïve animals. Phospho-ERK 1/2 expression was significantly decreased in the presence of inflammation plus tolerance. In contrast, no significant differences in phospho-p38 expression were observed between naïve and tolerant animals acutely injected with saline or morphine in presence of CFA inflammation. These results suggest that ERK but not p38 could be implicated in the development of morphine tolerance during peripheral inflammation. These experiments could contribute to establish the mechanisms implicated in the development of morphine tolerance in presence of inflammatory pain.