Brain reward circuits and relief of ongoing pain

大脑奖励回路和缓解持续疼痛

• 批准号: 8431853
• 负责人: Frank Porreca
• 金额: $ 56.79万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431853
• 关键词: Absence of pain sensation; Acute; Acute Pain; Affective; Animals; Anterior; Behavioral; Biological Markers; Brain; Cells; Cognitive; Data; Dimensions; Dopamine; Functional Magnetic Resonance Imaging; Human; Image; Injury; Investigation; Lesion; Lidocaine; Measurement; Mediating; Microdialysis; Microinjections; Modeling; Molecular Target; Morphine; Nerve Block; Nociception; Nucleus Accumbens; Opioid; Pain; Pathway interactions; Patients; Peripheral Nerves; Pharmaceutical Preparations; Postoperative Pain; Rattus; Rest; Rewards; Sensory; Signal Transduction; Speed; Stimulus; Surgical incisions; Time; Tyrosine 3-Monooxygenase; Ventral Tegmental Area; Work; base; chronic pain; cingulate cortex; dopaminergic neuron; expectation; experience; extracellular; human data; in vivo; injured; motivated behavior; neurochemistry; pre-clinical; pre-clinical research; preference; prevent; public health relevance; research study; response; reward processing; transmission process

DESCRIPTION (provided by applicant): Pain is a subjective, multi-dimensional experience with sensory, affective and cognitive components. The affective (aversive) dimensions of pain are the main complaint of patients. We have attempted to capture and mechanistically evaluate affective dimensions of ongoing pain in preclinical settings. The aversiveness of pain provides strong motivational drive to seek relief. Thus, treatments known to relieve pain clinically produce conditioned place preference selectively in injured animals, inferring activation of brain reward pathways. This possibility is consistent with human data that relief of pain is rewarding. In this application, we ask whether, and how, relief of ongoing pain might modulate brain reward circuits. Additionally, we explore whether manipulations that selectively target affective, rather than sensory, components of pain also activate reward circuits. We will use a rat model of time-dependent incisional pain to explore the potential activation of reward pathways by pain relief resulting from either peripheral nerve block (block of afferent input) or manipulations within the rostral anterior cingulate cortex (rACC, i.e., modulation of aversiveness without altering nociceptive input). We will use anatomical (IHC), neurochemical (in vivo microdialysis), behavioral and imaging (animal fMRI) analyses to characterize the functional activation of the nucleus accumbens (NAc)(Aim 1) and/or ventral tegmental area (VTA)(Aim 2) by pain relief or the expectation of relief. Functional connectivity between the rACC and the NAc that underlies motivated behavior to seek relief will be studied in Aim 3. Understanding circuits that reflect relief of ongoing pain will help to identify new molecular targets that may be exploited for discovery of therapies directly targeting affective dimensions of pain that may have increased translational relevance and ultimately validating a biomarker of pain relief (i.e., analgesia).

描述（由申请人提供）：疼痛是一种主观的、多维的体验，包括感觉、情感和认知成分。疼痛的情感（厌恶）维度是患者的主要主诉。我们试图捕捉并机械地评估临床前环境中持续疼痛的情感维度。对疼痛的厌恶提供了寻求缓解的强烈动机。因此，临床上已知的缓解疼痛的治疗方法 在受伤的动物中选择性地条件性位置偏好，推断大脑奖励通路的激活。这种可能性与人类数据一致，即缓解疼痛是有益的。在此应用中，我们询问持续疼痛的缓解是否以及如何调节大脑奖励回路。此外，我们还探讨了选择性针对疼痛的情感而非感觉成分的操作是否也会激活奖励回路。我们将使用时间依赖性切口痛的大鼠模型来探索通过周围神经阻滞（传入输入阻滞）或头侧前扣带皮层内的操作（​​rACC，即在不改变伤害性输入的情况下调节厌恶性）引起的疼痛缓解来激活奖赏通路的潜在作用。我们将使用解剖学 (IHC)、神经化学（体内微透析）、行为和成像（动物 fMRI）分析来表征伏隔核 (NAc)（目标 1）和/或腹侧被盖区 (VTA)（目标 2）通过疼痛缓解或缓解预期的功能激活。目标 3 将研究 rACC 和 NAc 之间的功能连接，该连接是寻求缓解的动机行为的基础。了解反映持续疼痛缓解的回路将有助于识别新的分子靶点，这些靶点可用于发现直接针对疼痛情感维度的疗法，这些疗法可能会增加转化相关性，并最终验证疼痛缓解的生物标志物（即镇痛）。