Understanding the functional role of kappa opioid receptor signaling in somatosensory neurons

慢性瘙痒和疼痛是一种使人衰弱的疾病，严重降低了全世界数百万人的生活质量，也是美国人寻求医疗救助的主要原因。然而，很少有治疗方法可以有效地减少瘙痒或疼痛而不引起严重的不良反应。这在一定程度上是因为目前的治疗方法作用于其机制尚不清楚的中心靶点。因此，增加我们对生理性瘙痒和疼痛调节的知识对于开发更安全，更有效的治疗方法至关重要。本研究旨在缩小这一差距，从而深入了解瘙痒和疼痛的外周调节。我们的实验室先前已经表明，kappa阿片样物质啡能抑制脊髓背侧的瘙痒。这种效应可能是由于，至少部分地，突触前抑制作用通过对脊髓初级感觉传入。我现在有初步的数据表明，外周选择性kappa阿片样物质可以抑制炎症性瘙痒和疼痛，降低热敏性，这表明KOR在初级传入神经元中传递这些感觉模式方面具有调节作用。因此，我假设外周选择性激动剂将通过KOR起作用，抑制炎症性瘙痒和疼痛，降低热敏性。本研究将通过解剖学、电生理学和行为学的方法来研究KOR信号在体感觉神经元中的功能作用。我将表征KOR-Cre+ DRG神经元，以确定分子身份，并可视化它们的外周和中枢投射（目的1）；使用膜片钳电生理学和光遗传学策略来分析初级传入是否表达KOR的功能水平，以及这些影响是发生在外周末梢、中枢末梢还是两者都发生（目的2）；并测量在存在或不存在外周选择性kappa阿片样物质的情况下对瘙痒和疼痛引起的刺激的行为反应的变化（目的3）。这些实验将阐明KOR信号在体感觉神经元上的功能，并有可能为慢性瘙痒和疼痛找到更安全、更有效的治疗靶点。

Chronic itch and pain are debilitating conditions that significantly decrease quality of life of millions worldwide and are primary reasons that Americans seek medical attention. Nevertheless, few treatments exist that effectively reduce itch or pain without causing severe adverse effects. This is, in part, because current therapies act on central targets whose mechanisms are poorly understood. Therefore, increasing our knowledge of the regulation of physiologic itch and pain is critical for developing safer and more effective therapies. This proposal aims to reduce this gap, thereby providing insight into the peripheral modulation of itch and pain. Our lab has previously shown that the kappa opioid dynorphin inhibits itch within the dorsal spinal cord. This effect may have been due, at least in part, to presynaptic inhibition via the action of dynorphin on primary sensory afferents in the spinal cord. I now have preliminary data indicating that peripherally selective kappa opioids may inhibit inflammatory itch and pain and reduce thermal sensitivity, suggesting a modulatory role for KOR in conveying these sensory modalities in primary afferent neurons. Therefore, I hypothesize that peripherally selective agonists will act through KOR to inhibit inflammatory itch and pain and reduce thermal sensitivity. This proposal will investigate the functional role of KOR signaling in somatosensory neurons through anatomical, electrophysiological, and behavioral approaches. I will characterize KOR-Cre+ DRG neurons to determine the molecular identity and visualize their peripheral and central projections (Aim 1); use patch-clamp electrophysiology and optogenetic strategies to analyze whether primary afferents express functional levels of KOR and whether these effects occur on peripheral terminals, central terminals, or both (Aim 2); and measure alterations in the behavioral responses to itch and pain-induced stimuli in the presence or absence of peripherally selective kappa opioids (Aim 3). These experiments will elucidate the function of KOR signaling on somatosensory neurons with the potential to identify safer, more effective therapeutic targets for chronic itch and pain.