Neuropeptide Y1 Receptor-Expressing Neurons in the Lateral Parabrachial Nucleus in Neuropathic Pain

项目摘要 疼痛是一种复杂的现象，它引起躯体感觉和运动反射反应， 以及情绪和自主神经状态的长期变化。虽然急性疼痛提供保护， 损伤、慢性或持久的疼痛，不提供保护功能，往往使人丧失能力。慢性疼痛 这些条件通过降低生活质量和创造环境，使患者、他们的家庭和社会变得虚弱。 巨大的财政后果，总额超过6300亿美元，每年为美国， 只有美国。神经性疼痛是一种类型的慢性疼痛，其由影响神经系统的病变或疾病引起。 躯体感觉系统，影响7-8%的总人口。然而，神经性疼痛是不好的， 对镇痛药物，包括阿片类药物，和治疗的替代疗法， needed.神经病理性疼痛的发展和维持的潜在机制是很差的 明白最近一波高调的出版物暗示臂旁核（PBN）作为一个感觉 疼痛和厌恶中枢PBN是一种小型的双侧脑桥脑结构，长期以来一直被认为 接收令人担忧的、有害的或威胁性的稳态信息，如味觉厌恶、伤害感受或 危险提示泰勒（UPitt）和贝特利（UPenn）实验室的初步数据表明， 表达神经肽Y（NPY）Y1受体（Npy 1 r表达）的三叉神经能PBN神经元 维持神经性疼痛。首先，应用冷（丙酮液滴）或轻擦（棉签） 在外周神经损伤后刺激小鼠的后爪产生显著的Fos激活， 表达Npy 1 r的PBN神经元。第二，药理学抑制PBNNpy 1 r表达神经元通过 NPY Y1 Gi受体的选择性激动剂减少神经性疼痛的行为症状，而 Npy 1 r表达神经元的化学发生激活产生条件性位置厌恶。三、应用 热刺激产生的钙瞬变在PBNNpy 1 r表达的神经元评估通过在体内纤维 测光法这些观察结果为我的中心假设提供了前提，即表达Npy 1 r的 PBN神经元子集对于神经性疼痛样行为是必需的。 具体目标1将利用体内纤维光度法和原位杂交评估PBN的活化 假手术和神经病动物中的npy 1 r表达神经元。 特异性目标2将应用体内化学遗传学来抑制假手术中PBN Npy 1 r表达神经元， 神经病动物，以评估他们的行为反射（机械和冷）和情感的必要性 （条件性位置偏好）疼痛的组成部分。 具体目标3将检查解剖（解剖追踪）和功能作用（抑制 化学遗传学）的脊髓上的目标PBNNpy 1 r表达传出投射，以揭示特定的 负责神经性疼痛的反射和情感成分的回路。

Project Summary Pain is a complex phenomenon that elicits somatosensory and motor reflexive responses together with marked and long-lasting changes in emotional and autonomic states. While acute pain provides protection from tissue damage, chronic or long-lasting pain, provides no protective function and is often incapacitating. Chronic pain conditions are debilitating to patients, their families, and society by reducing quality of life and creating enormous financial consequences that total more than 630 billion USD annually for the United States of America alone. Neuropathic pain is a type of chronic pain that arises from a lesion or disease affecting the somatosensory system and affects 7-8% of the general population. However, neuropathic pain is poorly responsive to analgesic drugs, including opioids, and alternative therapeutics for treatment are desperately needed. The underlying mechanisms of the development and maintenance of neuropathic pain are poorly understood. A recent wave of high-profile publications implicates the parabrachial nucleus (PBN) as a sensory hub for pain and aversion. The PBN is, a small, bilateral, pontine brain structure that has long been known to receive alarming, noxious, or threatening homeostatic information such as taste aversion, nociception, or danger cues. Promising preliminary data within the Taylor (UPitt) and Betley (UPenn) laboratories implicate glutamatergic PBN neurons expressing the neuropeptide Y (NPY) Y1 receptor (Npy1r-expressing) in the maintenance of neuropathic pain. First, application of a cool (acetone droplet) or light rub (cotton swab) stimulus to the hindpaw of a mouse following peripheral nerve injury produces significant Fos activation within Npy1r-expressing PBN neurons. Second, pharmacological inhibition of PBNNpy1r-expressing neurons via a selective agonist for the NPY Y1 Gi receptor reduces behavioral symptoms of neuropathic pain, whereas chemogenetic activation of Npy1r-expressing neurons produces conditioned place aversion. Third, application of a heat stimulus produces calcium transients in PBNNpy1r-expressing neurons assessed via in vivo fiber photometry. These observations provide the premise for my central hypothesis that the Npy1r-expressing subset of PBN neurons are necessary for neuropathic pain-like behaviors. Specific Aim 1 will utilize in vivo fiber photometry and in situ hybridization to assess the activation of PBN Npy1r-expressing neurons in both sham and neuropathic animals. Specific Aim 2 will apply in vivo chemogenetics to inhibit PBN Npy1r-expressing neurons in sham and neuropathic animals to assess their necessity for the behavioral reflexive (mechanical and cold) and affective (conditioned place preference) components of pain. Specific Aim 3 will examine both the anatomy (anatomical tracing) and functional role (inhibitory chemogenetics) of the supraspinal targets of PBNNpy1r-expressing efferent projections to uncover the specific ciruits responsible for both the reflexive and affective components of neuropathic pain.