Behavioral effects of deep brain stimulation in rats with chronic pain

深部脑刺激对慢性疼痛大鼠的行为影响

基本信息

批准号：
8310618
负责人：
THOMAS JEFFREY MARTIN
金额：
$ 22.2万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8310618
关键词：
Absence of pain sensation Acute Pain Alternative Therapies Amygdaloid structure Analgesics Animal Model Animals Anterior Anxiety Area Behavior Behavioral Biological Assay Brain Brain region Cell Nucleus Chronic Clinic Clinical Research Complex Data Deep Brain Stimulation Development Dose Electric Stimulation Electrodes Exploratory Behavior Filament Frequencies Future Genetic Gray unit of radiation dose Health Human Hypersensitivity Implant Investigation Laboratory Animals Lateral Ligation Mechanics Medial Mental Depression Modality Modeling Movement Disorders Nerve Operant Conditioning Opioid Pain Pain management Parkinson Disease Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Property Psychological reinforcement Rattus Research Rest Rewards Rodent Self Administration Self Stimulation Site Spinal nerve structure Stimulus Thalamic structure Therapeutic Translations United States Withdrawal allodynia chronic neuropathic pain chronic pain cingulate cortex clinical application drug efficacy effective therapy injured interest mechanical allodynia midbrain central gray substance nerve injury neurochemistry novel painful neuropathy pre-clinical preclinical study preference prescription opioid abuse productivity loss success technique development treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The objectives of this proposal are: (1) to examine novel brain regions in which deep brain stimulation (DBS) reverses mechanical allodynia in rats following spinal nerve ligation (SNL), and (2) to determine the brain regions in whic DBS produces rewarding and/or reinforcing effects in SNL rats using conditioned place preference or operant conditioning paradigms. In the search for novel targets for treatment of neuropathic pain, preclinical investigation using reflexive withdrawal from mechanical or thermal stimuli has produced few new therapies that have succeeded in the clinic. A variety of other behavioral endpoints have been proposed for investigation in laboratory animals with neuropathic pain, such as conditioned place preference and operant reinforcement with analgesics. The growing problem of prescription opioid abuse underscores the need to examine non-pharmacological strategies for treatment of neuropathic pain in addition to pharmacological approaches. Clinically, pain at rest has proven difficult to treat compared to elicited pain from external stimuli. Behaviors that are altered in rats following nerve injury othr than reflexive withdrawal from external stimuli include decreased exploratory behavior, increased anxiety-like behavior, conditioned place preference with analgesics, and analgesic self-administration. The proposed research will examine the effects of DBS on both elicited and non-elicited behaviors in rats with SNL using classical and novel behavioral endpoints. DBS has proven to be effective for treatment of neuropathic pain in humans to an extent, however improvement of this treatment modality has been hampered in part by the lack of preclinical studies in appropriate animal models that explore novel brain sites for potential clinical application. Preclinical studies of DBS have largely used acute pain models in rodents, however DBS is ineffective against acute pain states in humans. Therefore translation of the preclinical studies using DBS into the clinic has proven difficult. Preliminary data indicate that DBS maintains operant behavior in SNL rats only at stimulation parameters that reverse mechanical allodynia. The proposed studies will expand on these data and identify brain regions for which DBS reverses mechanical hypersensitivity in rats following nerve injury, and determine if DBS of these brain regions produces rewarding or reinforcing effects selectively in rats with neuropathic pain. Hopefully these studies will provide novel targets for clinical studies of DBS in patients with neuropathic pain, as well as provide a means for future studies that examine the mechanism of DBS-induced analgesia in laboratory animals. PUBLIC HEALTH RELEVANCE: Chronic pain is a growing health problem that is costly both in loss of productivity and treatment expense. The use of large doses of opioids for chronic pain treatment is associated with an increase in prescription opioid abuse. Discovery of new therapies for chronic pain has been limited and there is a need for novel preclinical approaches. Non-pharmacological approaches that have been tried in the clinic include deep brain stimulation, however progress has been hampered by a lack of preclinical studies that identify novel target regions. This proposal seeks to identify novel brain sites in which deep brain stimulation reverses mechanical allodynia in rats with chronic pain and selectively produces reward or reinforcement in nerve-injured rats.

描述（由申请人提供）：本提案的目的是：（1）检查新的大脑区域，其中深部脑刺激（DBS）可逆转脊髓神经结扎（SNL）后大鼠的机械异常性疼痛，以及（2）确定使用条件性位置偏好或操作性条件反射范式，DBS 在 SNL 大鼠中产生奖励和/或增强作用的大脑区域。在寻找治疗神经性疼痛的新靶标的过程中，利用机械或热刺激的反射性撤退进行的临床前研究几乎没有产生在临床上取得成功的新疗法。已经提出了各种其他行为终点用于对患有神经性疼痛的实验动物进行研究，例如条件性位置偏好和镇痛药的操作性强化。处方阿片类药物滥用问题日益严重，这凸显除了药物方法外，还需要研究治疗神经性疼痛的非药物策略。临床上，与外部刺激引起的疼痛相比，静息时的疼痛已被证明难以治疗。神经损伤后大鼠的行为发生改变，除了对外部刺激的反射性撤退之外，还包括探索行为减少、焦虑样行为增加、镇痛药条件性位置偏好以及镇痛自我给药。拟议的研究将使用经典和新颖的行为终点来研究 DBS 对 SNL 大鼠诱发和非诱发行为的影响。 DBS 已被证明在一定程度上对人类神经性疼痛的治疗有效，但这种治疗方式的改进在一定程度上受到了阻碍，因为缺乏在适当的动物模型中探索新的大脑部位以进行潜在临床应用的临床前研究。 DBS 的临床前研究主要使用啮齿类动物的急性疼痛模型，但 DBS 对人类的急性疼痛状态无效。因此，将使用 DBS 的临床前研究转化为临床已被证明是困难的。初步数据表明，DBS 仅在逆转机械异常性疼痛的刺激参数下维持 SNL 大鼠的操作行为。拟议的研究将扩展这些数据，并确定 DBS 在神经损伤后逆转大鼠机械过敏的大脑区域，并确定这些大脑区域的 DBS 是否选择性地对患有神经性疼痛的大鼠产生奖励或增强作用。希望这些研究能为临床研究提供新的靶点 DBS 在神经性疼痛患者中的作用，并为未来研究实验动物中 DBS 诱导镇痛的机制提供了一种手段。公共卫生相关性：慢性疼痛是一个日益严重的健康问题，造成生产力损失和治疗费用高昂。使用大剂量阿片类药物治疗慢性疼痛与处方阿片类药物滥用的增加有关。慢性疼痛新疗法的发现有限，需要新的临床前方法。临床上尝试过的非药物方法包括深部脑刺激，但由于缺乏识别新目标区域的临床前研究，进展受到阻碍。该提案旨在确定新的大脑部位，在这些部位中，深部脑刺激可以逆转慢性疼痛大鼠的机械性异常性疼痛，并选择性地对神经损伤的大鼠产生奖励或强化。