Project Summary The overall goal of this research is to better understand the how the kappa opioid receptor (KOR) system modulates cold hypersensitivity with the ultimate goal of uncovering a novel therapeutic target. Cold pain affects a number of diverse groups of patients and goes largely untreated. Neuropathic pain with cold allodynia is estimated to affect 15% to 50% of neuropathic pain patients. For many patients, cold pain is often a side effect that becomes a chronic debilitating condition. Patients undergoing chemotherapy using platinum-based drugs report increased sensitivity and pain to cold stimuli. Furthermore, heightened sensitivity to cold is problematic in those diagnosed with multiple sclerosis. For others, cold pain is part of larger more complex pain condition. The most commonly reported medications used to treat neuropathic pain are non-steroidal anti-inflammatory drugs (NSAIDs), opioids and anti-epileptics, which do not relieve or treat heightened cold sensitivity, primarily because we do not have clear understanding of the mechanisms involved in the modulation of cold pain. This research focuses on better understanding the mechanism by which peripheral KORs modulate cold hypersensitivity and cold pain. The first aim of this proposal will use combined transgenic and pharmacological approaches to assess the necessity of peripheral KOR expression in the modulation of cold hypersensitivity and cold pain. The second aim will determine the mechanism by which KORs in dorsal root ganglion can modulate TRPA1 signaling, as well as determine the necessity of the involvement of TRPA1 channels in KOR mediated cold hypersensitivity. The third aim will test whether KORs in dorsal root ganglion also modulate TRPM8 signaling. In the final aim, will use human dorsal root ganglion tissue from organ donors to determine if the KOR-modulation of TRP function exists in humans. Together, these approaches will allow us to dissect the role of peripheral kappa opioids in