Kappa opioid signaling in somatosensation

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Project Summary/Abstract Opioids — mu, kappa, and delta—are important regulators of somatosensation, including pain, itch, and touch (1). In particular, recent studies suggest that heat-sensitive primary afferents express the mu opioid receptor (MOR), whereas mechanically sensitive primary afferents express the delta opioid receptor (DOR) (2, 3). In contrast, the primary afferent subtypes that express the kappa opioid receptor (KOR) are completely unknown. Addressing this gap in knowledge is important because peripherally selective kappa agonists are currently being tested in clinical trials, yet the cellular targets of these drugs have not been defined (4). To address this issue, we recently generated a KOR-Cre knock-in mouse to define the primary afferents that express KOR and investigate their function in somatosensation (5). Surprisingly, we discovered KOR-Cre expression in an unexpected population of primary afferents: low-threshold mechanoreceptors that form either lanceolate or circumferential endings around hair follicles. These findings raise the possibility that kappa opioid signaling within primary afferents modulates light touch. Here, I propose to elucidate the role of KOR signaling in primary sensory afferent function using a combination of immunohistochemistry, optogenetics, and electrophysiology. In particular, I will test the hypothesis that kappa opioid signaling inhibits the activity of low-threshold mechanoreceptors. Specifically, I will 1) define the primary afferents that express KOR; 2) test the function of KOR signaling in these cells; and 3) test the role of KOR signaling on synaptic transmission into the dorsal horn. Understanding the population(s) of primary afferents that express KOR may have important clinical implications for the treatment of allydonia, a type of pain that is refractory to current therapies.