Cellular, synaptic, and network adaptations of MCL addiction and motivation circuits (NAc, VTA, PAG) with chronic pain and opioid exposure

MCL 成瘾和动机回路（NAc、VTA、PAG）与慢性疼痛和阿片类药物暴露的细胞、突触和网络适应

• 批准号: 10198886
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 31.14万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198886
• 关键词: Affect; Amygdaloid structure; Anatomy; Attenuated; Behavior; Behavioral; Brain; Cells; Collaborations; Complement; Cues; Dopamine D1 Receptor; Dopamine D2 Receptor; Drug Addiction; Drug abuse; Electrophysiology (science); Epidemic; Excitatory Synapse; Extinction (Psychology); Goals; Hippocampus (Brain); Human; Label; Lesion; Link; Medial; Modeling; Modernization; Molecular; Morphine; Motivation; Mus; Neurobiology; Neurons; Nociception; Nucleus Accumbens; Opioid; Optics; Pain; Pharmaceutical Preparations; Physiological; Play; Prefrontal Cortex; Property; Protocols documentation; Psychological reinforcement; Rewards; Rodent; Role; Schedule; Self Administration; Shapes; Signal Transduction; Slice; Source; Synapses; Testing; Time; Training; Transgenic Mice; Ventral Tegmental Area; Withdrawal; Work; addiction; attenuation; chronic back pain; chronic pain; chronic pain patient; disability; dopaminergic neuron; drug seeking behavior; experimental study; insight; mouse model; nerve injury; novel therapeutics; opioid abuse; opioid exposure; optogenetics; pain behavior; paraventricular nucleus; prescription opioid; spared nerve; synergism; tool

Chronic pain is the top source of disability in the U.S. and is commonly treated with opiates. Many chronic pain patients given prescription opiates for treatment struggle with addiction and the abuse of opioids has reached epidemic proportions in the U.S. The neurobiological basis for the connection between chronic pain and opioid abuse is uncertain. However, recent work has shown that chronic pain is shaped by the same mesolimbic circuitry underlying drug addiction. The ventral tegmental area (VTA) and nucleus accumbens (NAc) appears to be critical hubs of this circuitry. Their role in drug addiction is well-established. What is new is that they also play key roles in chronic pain. We have shown that in the rodent spared nerve injury (SNI) model of chronic pain there are cell-specific and region-specific adaptations in the NAc that include both intrinsic and synaptic changes. These changes were causally linked to pain behavior and alterations in the activity of dopaminergic neurons in the VTA. Although there are clear effects of opioids on the VTA and NAc, how opioids shape SNI-induced adaptations in the NAc is completely unexplored. Moreover, it is unclear how chronic pain modifies the addictive potential of opioids. In Project 2, our over-arching goal is to fill these gaps in our understanding. To this end, an array of modern behavioral, anatomical, physiological and molecular approaches will be used in mouse models to achieve four specific aims: Specific Aim 1: To determine whether morphine reinforcement and seeking behavior is enhanced in SNI mice trained to self-administer morphine. Our working hypothesis is that SNI will increase the reinforcing efficacy of morphine and drug seeking behavior. Specific Aim 2: To determine whether SNI differentially affects VTA DA neurons innervating the medial shell and core of the NAc and whether these effects are modulated by morphine self-administration (MSA). Our working model is that VTA regions innervating the msNAc and cNAc are non-overlapping and respond in largely opposing ways to SNI. Moreover, we hypothesize that short-term MSA will diminish SNI-induced adaptations. Specific Aim 3: To determine whether short-term (5d) morphine self-administration alters SNI-induced adaptations in specific NAc circuits. Our working hypothesis is that MSA shortly after SNI will dampen ascending nociceptive signaling and attenuate alterations in the activity of VTA, resulting in only modest adaptations in msNAc/cNAc circuits. Specific Aim 4: To determine whether long-term (14 d) morphine self- administration and withdrawal alters SNI induced adaptations in specific NAc circuits. Our working hypothesis is that with time the beneficial effects of morphine on VTA and NAc circuits will wane, leading to augmentation of SNI-induced adaptations in NAc circuits, resulting in enhanced morphine reward and drug seeking. The studies outlined for these four aims should provide fundamental new insights into the mechanisms by which chronic pain increases the potential for addiction to opioids, like morphine, and in so doing point to novel therapies. Moreover, these aims complement those of Projects 1, 3 and 4, creating an opportunity for synergy.

慢性疼痛是美国致残的首要原因，通常用阿片类药物治疗。许多慢性疼痛患者