Behavioral effects of deep brain stimulation in rats with chronic pain

描述(由申请人提供)：本建议的目标是：(1)研究深部脑刺激(DBS)逆转脊神经结扎(SNL)后大鼠机械性痛觉异常的新脑区，以及(2)利用条件性位置偏爱或操作性条件反射范式，确定DBS在SNL大鼠中产生奖赏和/或增强效应的脑区。在寻找治疗神经病理性疼痛的新靶点方面，使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成功的新疗法。在神经病理性疼痛的实验动物中，已经提出了各种其他行为终点的研究，如条件性位置偏爱和镇痛剂的操作强化。处方阿片类药物滥用问题的日益严重突出表明，除了药理学方法外，还需要审查治疗神经病理性疼痛的非药理学策略。在临床上，与外部刺激引起的疼痛相比，休息时的疼痛被证明很难治疗。神经损伤后大鼠的行为改变不是外界刺激的反射性撤退，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爱，以及止痛剂的自我给药。这项拟议的研究将使用经典和新的行为终点来检验DBS对SNL大鼠诱发性行为和非诱发性行为的影响。DBS已被证明在一定程度上对人类神经病理性疼痛的治疗有效，但这种治疗方式的改进在一定程度上受到缺乏适当动物模型的临床前研究的阻碍，这些动物模型探索潜在的临床应用的新的大脑部位。DBS的临床前研究主要使用啮齿类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，使用DBS将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仅在逆转机械性痛觉异常的刺激参数下才能维持SNL大鼠的操作行为。拟议的研究将在这些数据的基础上扩展，确定DBS逆转神经损伤后大鼠机械过敏的大脑区域，并确定这些大脑区域的DBS在神经病理性疼痛的大鼠中是否有选择地产生奖励或增强效果。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应用，以及为未来研究DBS在实验动物中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，在生产力损失和治疗费用方面都代价高昂。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。慢性疼痛的新疗法的发现一直是有限的，需要新的临床前方法。已在临床上尝试的非药理学方法包括脑深部刺激，但由于缺乏确定新靶区的临床前研究，进展受到阻碍。这项建议旨在确定新的大脑部位，在这些部位，深部脑刺激可以逆转慢性疼痛大鼠的机械性超感痛觉，并选择性地在神经损伤大鼠中产生奖励或强化。

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.