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

慢性瘙痒和疼痛是使人虚弱的疾病，显著降低了全球数百万人的生活质量，也是美国人寻求医疗服务的主要原因。然而，很少有治疗方法可以有效地减轻瘙痒或疼痛，而不会造成严重的不良反应。这在一定程度上是因为目前的治疗方法作用于中心靶点，而这些靶点的机制尚不清楚。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和更有效的治疗方法至关重要。这项建议旨在缩小这一差距，从而提供对瘙痒和疼痛的外周调制的洞察。我们的实验室以前已经证明，kappa阿片类强啡肽抑制背侧脊髓内的瘙痒。这种效应可能至少部分归因于强啡肽对脊髓初级感觉传入的突触前抑制作用。我现在有初步数据表明，外周选择性kappa阿片类药物可以抑制炎性瘙痒和疼痛，并降低热敏感性，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制作用。因此，我假设外周选择性激动剂将通过KOR发挥作用，以抑制炎症性瘙痒和疼痛，并降低热敏感性。这项建议将通过解剖学、电生理学和行为学的方法研究KOR信号在躯体感觉神经元中的功能作用。我将鉴定KOR-CRE+DRG神经元，以确定其分子身份并显示其外周和中央投射(目标1)；使用膜片钳电生理学和光遗传学策略分析初级传入是否表达KOR的功能水平，以及这些影响是否发生在外周终末和/或中央终末(目标2)；以及测量在存在或不存在外周选择性kappa阿片样物质的情况下，对瘙痒和疼痛诱导刺激的行为反应的变化(目标3)。这些实验将阐明KOR信号在体感神经元上的功能，有可能找到更安全、更有效的治疗慢性瘙痒和疼痛的靶点。

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.