Brain reward circuits and relief of ongoing pain

描述(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)维度是患者的主要抱怨。我们试图捕捉和机械地评估临床前环境中持续疼痛的情感维度。对痛苦的厌恶提供了寻求解脱的强大动力。因此，已知的缓解疼痛的治疗方法在临床上产生 条件性位置偏爱在受伤动物中的选择性，推断大脑奖赏通路的激活。这种可能性与人类数据一致，即缓解疼痛是有回报的。在这一应用中，我们询问持续疼痛的缓解是否以及如何可能调节大脑奖赏回路。此外，我们还探讨了选择性地针对疼痛的情感成分而不是感觉成分的操作是否也激活了奖赏回路。我们将使用一个时间依赖的切口痛的大鼠模型来探索通过周围神经阻滞(传入输入的阻断)或嘴前扣带皮质内的操作(rACC，即在不改变伤害性输入的情况下调节厌恶)所引起的疼痛缓解而激活奖励通路的可能性。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)分析来表征疼痛缓解或缓解预期对伏隔核(NAC)(目标1)和/或腹侧被盖区(VTA)(目标2)的功能激活。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。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，这些靶点可能被用于发现直接针对疼痛的情感维度的疗法，这些疗法可能已经增加了翻译相关性，并最终验证了疼痛缓解的生物标记物(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).