Behavioral effects of deep brain stimulation in rats with chronic pain

描述（申请人提供）：本提案的目的是：（1）检查脑深部电刺激（DBS）逆转脊神经结扎（SNL）后大鼠的机械性异常性疼痛的新脑区域，（2）确定DBS产生奖赏和/或刺激的脑区。或强化效应的SNL大鼠使用条件性位置偏爱或操作性条件反射范式。在寻找治疗神经性疼痛的新靶点时，使用从机械或热刺激反射性退缩的临床前研究产生了很少在临床上成功的新疗法。已经提出了各种其他行为终点的研究在实验室动物与神经性疼痛，如条件性位置偏爱和操作性强化与镇痛药。处方阿片类药物滥用的问题日益严重，强调需要检查非药理学策略治疗神经性疼痛，除了药理学方法。临床上，与外部刺激引起的疼痛相比，静息疼痛已被证明难以治疗。 神经损伤后大鼠的行为改变，而不是从外部刺激反射性退缩，包括探索行为减少，焦虑样行为增加，镇痛剂的条件性位置偏好和镇痛剂自我给药。拟议的研究将使用经典和新的行为终点来检查DBS对SNL大鼠的诱发和非诱发行为的影响。DBS已被证明在一定程度上可有效治疗人类神经性疼痛，但这种治疗方式的改进部分受到缺乏适当动物模型临床前研究的阻碍，这些动物模型探索了潜在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保持操作行为在SNL大鼠只有在刺激参数，扭转机械异常性疼痛。 拟议的研究将扩展这些数据，并确定脑区域DBS逆转神经损伤后大鼠的机械超敏反应，并确定这些脑区域的DBS是否选择性地在神经性疼痛大鼠中产生奖励或强化作用。希望这些研究将为临床研究提供新的靶点 DBS在神经病理性疼痛患者中的作用，并为将来在实验室动物中检查DBS诱导镇痛机制的研究提供了一种手段。

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.