Circuits in descending facilitation of nociception

伤害感受下降促进电路

• 批准号: 7426358
• 负责人: MARTIN W. WESSENDORF
• 金额: $ 27.15万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7426358
• 关键词: Absence of pain sensation; Afferent Neurons; Analgesics; Animal Model; Axon; Caliber; Cells; Cholecystokinin; Cholecystokinin Receptor; Chromosome Pairing; Disinhibition; Dorsal; Electric Stimulation; Electrophysiology (science); Enkephalins; Figs - dietary; Fire - disasters; Glutamate Receptor; Glutamates; Goals; Hyperalgesia; In Situ Hybridization; Inflammation; Interneurons; Left; Link; Mediating; Mediation; Neurons; Neuropeptides; Neurotransmitters; Nociception; Opiates; Pain; Play; Rattus; Reporting; Role; Scheme; Serotonin; Spinal; Spinal Cord; Spinal cord posterior horn; Spinothalamic Tracts; Synapses; Synaptic Receptors; Testing; Tetragastrin; allodynia; dorsal horn; gamma-Aminobutyric Acid; immunocytochemistry; in vivo; painful neuropathy; presynaptic

DESCRIPTION (provided by applicant): Neurons in the rostral portion of the ventromedial medulla (RVM) inhibit nociception in animal models of pain and play a key role in mediation of opiate analgesia. In addition, though, it has been shown that spinally projecting neurons in the RVM can facilitate nociception. Descending facilitatory neurons may mediate hyperalgesia due to inflammation; allodynia associated with neuropathic pain and may underlie aspects of opiate tolerance. However, the neurotransmitters and circuits by which descending facilitation occurs are not known. Spinally projecting neurons expressing glutamate and cholecystokinin (CCK), 2 excitatory neurotransmitters, have been reported in the RVM; Spinal glutamate receptors and CCK receptors have been reported to facilitate nociception. Thus, we propose in this application that RVM neurons expressing glutamate and/or CCK directly excite spinal nociceptive neurons. The Specific Aims of this application test corollaries of that proposition using a combination of tract-tracing, immunocytochemistry, in situ hybridization, and in vivo electrophysiology. In Aims 1 and 2 we propose to test whether RVM neurons containing glutamate and/or CCK innervate the spinal dorsal horn, including marginal zone and spinothalamic tract (STT) neurons. In Aim 3, we propose to test whether spinal cord marginal zone neurons, STT neurons and primary afferent neurons express receptors for CCK. Aim 4 proposes to test whether nociceptive neurons in rats are excited by CCK; Aim 5 proposes to determine whether spinal CCK antagonists reduce the nociceptive facilitation of spinal neurons evoked by stimulation of the RVM. Testing these hypotheses will clarify the role of spinally projecting glutamatergic and CCK RVM neurons in descending facilitation and may suggest strategies by which pain and opiate tolerance can be reduced.

描述（由申请人提供）：腹侧髓质（RVM）延髓部分的神经元抑制疼痛动物模型中的伤害感，并在鸦片镇痛的介导中起关键作用。不过，此外，已经显示RVM中的跨度突出神经元可以促进伤害感受。下降的促进性神经元可能会导致炎症引起的痛觉过敏。与神经性疼痛相关的异常性疾病，可能是阿片类药物耐受性的方面。然而，尚不清楚发生降级促进的神经递质和电路。在RVM中报道了表达谷氨酸和胆囊动蛋白（CCK）的旋转神经元（CCK）（CCK），已在RVM中报道。据报道，脊柱谷氨酸受体和CCK受体可促进伤害感受。因此，我们在此应用中提出，表达谷氨酸和/或CCK的RVM神经元直接激发脊柱伤害性神经元。该应用测试推论的特定目的是使用道追踪，免疫细胞化学，原位杂交和体内电生理学的结合。在目标1和2中，我们建议测试含有谷氨酸和/或CCK的RVM神经元是否支配脊柱背角，包括边缘区和脊柱丘脑区（STT）神经元。在AIM 3中，我们建议测试CCK的脊髓边缘区域神经元，STT神经元和原发性传入神经元的表达受体。 AIM 4提议测试大鼠中的伤害感受神经元是否受到CCK的激发。 AIM 5提出，确定脊柱CCK拮抗剂是否减少了通过刺激RVM引起的脊柱神经元的伤害感受促进。对这些假设进行检验将阐明旋转投射谷氨酸能和CCK RVM神经元在下降促进中的作用，并可能提出可以降低疼痛和鸦片耐受性的策略。