SUMMARY The opioid pandemic highlights the urgent needs to understand pain mechanisms and identify novel, non-opioid therapeutic targets to treat pain. Ion channels involve in almost all aspects of pain sensation. Therefore, targeting ion channels has been considered as one of the most promising strategies to replace opioid analgesics for pain treatment. However, most of ion channels are widely expressed in the nervous system. Thus, how to specifically target ion channels in pain transmission pathway without affecting their other critical functions becomes a bottleneck in translating this strategy into clinical applications. Interestingly, the activities of many ion channels are controlled by their cell-type specific regulatory proteins. Targeting these regulatory proteins to control ion channels in pain pathways thus presents a novel and highly specific approach to prevent ion channels-mediated pain with minimal to no side effects. Our preliminary results showed that Lrrc55, an understudied regulatory subunit of BK potassium channel, is expressed in a subset of dorsal root ganglion (DRG) neurons and spinal cord lamina i-ii neurons. Our preliminary data also demonstrated that knockout of Lrrc55 abolishes mechanical pain without affecting thermal heat pain in an inflammatory pain model and a nerve injury pain model. Our findings suggest that LRRC55 might be a novel candidate target for treating pain, possibly selective for mechanical pain. In this high-risk, high-reward application, two investigators will bring complementary and unique expertise in ion channel biology and pain to: 1) delineate LRRC55’s roles in chronic pain behaviors using the Lrrc55 deficient mice; 2) quantify functional changes of Lrrc55 expression in DRG and spinal cord neurons after chronic pain; and 3) test if knockdown of Lrrc55 in DRG and spinal cord neurons can be an effective strategy to suppress chronic pain. Our study will be the first to demonstrate LRRC55’s neurological function in pain. More importantly, success of this project can open a new avenue to develop novel and specific therapeutics to target cell-type specific ion channel regulatory proteins to replace opioid-based pain killers.