Cellular and Molecular Mechanisms of Regenerative Pain Medicine

Abstract

Pain is the most common reason for physician office visits worldwide and one in three Americans may suffer from chronic pain, with annual costs exceeding $600 billion in the United States. Despite their addiction liability, opioids have been the most prescribed analgesics for the treatment of severe pain, such as postoperative pain and cancer pain. Current pharmacological therapies for chronic pain are lacking in clinical efficacy and safety profile, and they were developed prior to our emerging understanding of sexual dimorphism in chronic pain symptomology and treatment. In my thesis study, we explored three non-pharmacological approaches with a specific focus on the cellular and molecular mechanisms on regenerative pain medicine: 1) bone marrow stromal cells (BMSCs), 2) conditioned serum (CS) or autologous conditioned serum (ACS), and 3) dual-frequency spinal cord stimulation (SCS). Each of these treatments were found to provide long-term analgesic effects in animal models of chronic neuropathic pain, with unique aspects in their respective mechanisms across pain modalities, sexes, and species, which included secretion of anti-inflammatory cytokines notably TGF-beta 1, generation of nanoscale secretory exosomes with profound analgesic and pain resolution properties, and broad immune gene activation extending the time-course of analgesia via neutrophil and S100A8/A9 signaling. The findings of my thesis study strongly suggests that novel regenerative pain therapies may provide superior analgesic efficacy versus current treatments by directly addressing the causes of chronic pain through neuroimmune mechanisms.