Explore the role of a new chemokine to alleviate postoperative pain

Project summary/Abstract. Chronic postoperative pain affects millions of Americans every year. Postoperative pain management is a clinical challenge; 10-20% of patients do not receive adequate pain relief and opioid-based medications may lead to opioid dependence. The immune system plays a critical role in the development of pain. Targeting peripheral immune mediators represents an attractive therapeutic strategy without the disadvantage of central nervous system (CNS)-associated side effects. Our preliminary data revealed that blocking CCL12 alleviated postoperative pain and conversely administration of CCL12 induced nociception. CCL12 has never been investigated in preclinical pain research. Its receptor CCR2 is expressed in sensory neurons and immune cells. We hypothesize that targeting CCL12 is effective and safe to reduce pain after surgery. Our first specific aim will test that neutralizing CCL12 is antinociceptive in two clinically relevant postoperative pain models and that neutralizing CCL12 does not affect morphine analgesia and reward. Our second specific aim will explore the mechanisms by which CCL12 induces nociception. More specifically, we will investigate the cellular target of CCL12. Success in this project could identify CCL12 as a promising target for managing surgical pain, offering a safer alternative to opioids. Understanding how CCL12 influences pain mechanisms would advance neuroimmunology and potentially lead to more effective pain treatments. Unlike previous approaches targeting CCR2, which yielded mixed results, focusing on CCL12 may offer a more precise solution. Local administration of CCL12-neutralizing antibodies could provide targeted pain relief without central nervous system side effects, presenting a significant advancement in peri- and postoperative pain management.