Peripheral Mechanisms of Kappa Opioid Receptor-Mediated Cold Hypersensitivity

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 cold
hypersensitivity and cold pain. Understanding the mechanisms by which the KOR system modulates cold
hypersensitivity and how this system may also be involved in modulation of cold pain will have major implications
not only in our understanding of basic mechanisms of cold hypersensitivity, but may also open up alternative
therapeutic targets to allow us to treat cold hypersensitivity and pain.

Grant Number: 5R01NS123070-04
NIH Institute/Center: NIH
Principal Investigator: Ream Al-Hasani