Brain reward circuits and relief of ongoing pain

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。我们试图在临床前环境中捕获和机械地评估持续疼痛的情感维度。对疼痛的厌恶提供了寻求缓解的强大动力。因此，已知的缓解疼痛的治疗在临床上产生 在受伤的动物中选择性地产生条件性位置偏爱，推断大脑奖赏通路的激活。这种可能性与人类数据一致，即缓解疼痛是有益的。在这个应用程序中，我们要问的是，持续疼痛的缓解是否以及如何调节大脑的奖励回路。此外，我们探讨是否有选择性地针对情感，而不是感官，疼痛的组成部分也激活奖励电路的操作。我们将使用时间依赖性切口疼痛的大鼠模型来探索通过由外周神经阻滞（传入输入的阻滞）或头端前扣带皮层（rACC，即，在不改变伤害性输入的情况下调节厌恶性）。我们将使用解剖学（IHC），神经化学（在体内微透析），行为和成像（动物功能磁共振成像）分析，以表征的功能激活的延髓核（NAc）（目标1）和/或腹侧被盖区（VTA）（目标2）的疼痛缓解或缓解的期望。目标3将研究rACC和NAc之间的功能连接，这是寻求缓解的动机行为的基础。理解反映持续疼痛缓解的回路将有助于鉴定新的分子靶标，所述新的分子靶标可用于发现直接靶向疼痛的情感维度的疗法，所述疼痛的情感维度可具有增加的翻译相关性，并最终验证疼痛缓解的生物标志物（即，镇痛）。

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).