| Opioids are considered the gold standard in treating pain. Patients prescribed morphine for the management of chronic pain also present with complications such as increased susceptibility to opportunistic infections and inadequate healing of wounds. Yet, an in vivo model useful in elucidating mechanisms' underlying this phenomenon has not been established.;Through the standardization of an in vivo wound murine model, our laboratory has characterized the suppressive effects of morphine on wound healing events in the presence of an infection. Our model is the first to mimic the clinical manifestations of bacterial or viral infection seen in opioid user and abuser populations. Our findings show a marked decrease in wound closure and integrity following chronic morphine administration in the presence of LPS or the HIV-1 protein Tat.;In respect to the bacterial infection model, a delay in neutrophil infiltration/decrease in macrophage infiltration into the wound beds was also seen. Interestingly, the macrophage chemoattractant MCP-1 levels were significantly decreased following chronic morphine treatment whereas no modulation was seen for the neutrophil chemoattractant MIP-2. Neutrophil chemotaxis towards a chemical gradient showed morphine's suppressive effects occurring directly on the immune cell, as well as, on the expression of chemoattractant factors independent of MIP-2.;When investigating the possible role chronic morphine plays on later stages of wound healing, we employed an angiogenesis model. Findings suggest morphine suppresses new blood vessel formation and expression of the proangiogenic factors HIF-1alpha and VEGF.;In our HIV-1 Tat model, our data implicates an immune suppression in wound healing events following HIV-1 protein Tat and chronic morphine co-treatment and shows the potentially detrimental effects chronic morphine administration may have in the wound healing processes of HIV positive patients.;Taken together, these findings indicate that the mechanism by which morphine exerts its immunosuppressive effects on pro-inflammatory responses varies depending on the immune cell type and depending on the type of infectious agent present. Morphine's suppression of early stage innate immunity, critical in determining the outcome of pathogen resolution in wounds, shifts the outcome to a persistence of pathogen onboard, prolonged inflammation, pathogen dissemination and inadequate wound healing. |
