Behavioral effects of deep brain stimulation in rats with chronic pain

描述（由申请人提供）：本提案的目标是：(1)检查脑深部刺激（DBS）逆转脊髓神经结扎（SNL）后大鼠机械性异常痛的新脑区域，(2)确定脑深部刺激（DBS）使用条件位置偏好或操作性条件反射范式在SNL大鼠中产生奖励和/或强化效应的脑区域。在寻找治疗神经性疼痛的新靶点的过程中，使用机械或热刺激的反射性退缩的临床前研究已经产生了一些在临床上成功的新疗法。在实验动物神经性疼痛的研究中，已经提出了多种其他行为终点，如条件位置偏好和镇痛药的操作性强化。处方阿片类药物滥用日益严重的问题强调了除了药理学方法外，还需要研究治疗神经性疼痛的非药物策略。临床证明，与外界刺激引起的疼痛相比，静息疼痛难以治疗。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退缩外，还包括探索行为减少、焦虑样行为增加、使用镇痛药的条件性位置偏好和镇痛药自我给药。本研究将采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已被证明对人类神经性疼痛的治疗在一定程度上是有效的，然而，这种治疗方式的改善一直受到阻碍，部分原因是缺乏在适当的动物模型中进行临床前研究，以探索潜在的临床应用的新脑部位。DBS的临床前研究主要使用啮齿动物的急性疼痛模型，然而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仅在能逆转机械异常性疼痛的刺激参数下才能维持SNL大鼠的操作行为。拟议的研究将扩展这些数据，并确定DBS逆转神经损伤后大鼠机械超敏反应的脑区域，并确定这些脑区域的DBS是否在神经性疼痛大鼠中选择性地产生奖励或强化作用。希望这些研究能为临床研究提供新的靶点

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.