Investigating the Neural Circuits of Itch

描述（由申请人提供）：慢性瘙痒（脓疱炎）是一种严重的疾病，会导致生活质量严重下降。此外，这种情况比人们普遍认为的要普遍得多，这是去看皮肤科医生的最常见原因，尽管事实上治疗通常是无效的。然而，虽然瘙痒是由皮肤引起的，但它不仅仅是一种皮肤状况。更确切地说，瘙痒是一种复杂而鲜为人知的感觉，它是由周围神经回路、脊髓和大脑介导的。因此，长期来看

DESCRIPTION (provided by applicant): Chronic itch (puritis) is a severe condition that results in severely diminished quality of life. Moreover, this condition is much more widespread than generally appreciated, representing the most common reason to visit a dermatologist, despite the fact that treatments are generally ineffective. However, while itch is initiated in the skin, i is more than just a skin condition. Rather, itch is a complex and poorly understood sensation that is mediated by neural circuits in the periphery, the spinal cord and the brain. Thus, the long-term goal of our research is to gain a better understanding of the neural circuits that mediate itch wit the view of developing more effective therapies for puritis. We previously discovered that the transcription factor Bhlhb5 is required for the survival of a subset of inhibitory interneurons in he spinal cord (which are here termed B5-I neurons) that are required for normal itch sensation; mice lacking these spinal interneurons suffer from persistent pathological itch. Since B5-I neurons are the first component of an itch circuit to be labeled genetically, studying these neurons provides us with a unique opportunity to unravel the neural basis of itch. Importantly, we have recently discovered that B5-I neurons are a specific subset of spinal interneurons that express dynorphin. This finding is important because dynorphin is a kappa opioid receptor (KOR) agonist, and KOR agonists have recently been shown to relieve itch in rodents and man. We therefore hypothesize that B5-I neurons function to inhibit itch, and that they do so in part through the release of dynorphin in the spinal cord. Here we propose to test this hypothesis in through 3 specific aims: Aim 1: Determine the degree to which B5-I neurons are specific to the regulation of itch. Aim 2: Dissect neural circuits in the dorsal horn using B5-I neurons as a molecular handle. Aim 3: Define the role of spinal dynorphin in itch. Results from these experiments are likely to have major clinical implications for people that suffer from chronic itch because our findings will define a key cellular target for the development of future anti-itch therapies and they will provide important insight into the mechanism of KOR-mediated inhibition of itch.