Measurement of pain-suppressed behaviors in rodent models of chronic pain

慢性疼痛啮齿动物模型中疼痛抑制行为的测量

• 批准号: 7253576
• 负责人: Glenn W. Stevenson
• 金额: $ 21.2万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253576
• 关键词: Absence of pain sensation; Academic Research Enhancement Awards; Acetic Acid; Acetic Acids; Acids; Acute; Acute Pain; Adaptive Behaviors; Address; Adverse effects; Agonist; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Behavioral; Biological Assay; Caffeine; Catalepsy; Central Nervous System Stimulants; Characteristics; Class; Classification; Clinical; Clinical Drug Development; Clinical Medicine; Clinical Trials; Complement; Daily; Data; Data Collection; Degenerative polyarthritis; Development; Dopamine Antagonists; Dose; Effectiveness; End Point; Environment; Exercise; Goals; Grant; Haloperidol; Human; Inflammatory; Injection of therapeutic agent; Intervention; Iodoacetates; Ketoprofen; Laboratories; Lead; Locomotion; Mammals; Measures; Mediating; Methods; Modeling; Morphine; Motor; Motor Activity; Mus; Neurobiology; New England; Opioid; Opioid Analgesics; Pain; Pain Measurement; Patients; Pharmaceutical Preparations; Phase; Population; Pre-Clinical Model; Preclinical Testing; Preparation; Procedures; Public Health; Reporting; Research; Research Design; Rodent; Rodent Model; Running; Scientist; Sensory; Standards of Weights and Measures; Stimulus; Testing; Therapeutic Effect; Therapeutic Index; Thinking; Time; Treatment Effectiveness; Universities; Validation; Walking; Withdrawal; career; chronic pain; clinically relevant; design; experience; feeding; motor impairment; painful neuropathy; pre-clinical; preclinical study; prescription document; prescription procedure; programs; prototype; rat Ran 2 protein; response

DESCRIPTION (provided by applicant): Prescription opioid analgesics and non-steroidal anti-inflammatory drugs are frontline treatments for chronic pain. However, inconsistent therapeutic effects and/or side effects limit their use. Development of better analgesics requires predictive and reliable preclinical (animal) models for pain. Although pain is typically associated with pain-evoked behaviors (e.g. withdrawal responses), and pain-suppressed behaviors (e.g. decreases in normally adaptive behaviors like feeding, locomotion, exercise), current preclinical pain models rely almost exclusively on pain-evoked behaviors. This approach has at least two limitations. First, although assays of pain-evoked behavior are thought to be predictive of many acute pain states, they may lack clinical relevance as models of chronic pain. In support of this, assessment of chronic pain in clinical medicine (both human and veterinary) relies heavily on measurement of pain-suppressed behavior to assess the presence and impact of pain, and the effectiveness of treatment. Second, drugs may decrease pain-evoked behaviors not only by reducing the sensory experience of pain (true analgesia), but also by producing motor impairment, which results in "false positive" effects. A primary goal of this Academic Research Enhancement Award (AREA) application is to address these limitations by developing and validating new animal models that can assess preclinical analgesic efficacy using measures of pain-suppressed behaviors in rodents. A secondary goal of this application is to help facilitate the new PI's career as an independent scientist, and to help further strengthen the undergraduate research environment at the University of New England. It is hypothesized that models of pain-suppressed behavior may capture clinically important aspects of pain that can be missed using standard assays of pain-evoked behaviors. It is also hypothesized that drugs producing motor impairment would not produce "false positive" analgesic effects in such models. In support of these hypotheses, preliminary data are presented demonstrating that locomotor activity can be reliably suppressed by a standard sub-acute noxious stimulus (i.p. injection of acetic acid), and that pain-suppressed locomotor activity can be selectively restored by a prototype analgesic drug (morphine). I will further validate and extend these findings according to 2 specific aims: (1) Evaluate the effects of osteoarthritis-induced pain on locomotor activity and wheel running and (2) Assess analgesic and non-analgesic drugs on the observed pain-suppressed behaviors in an effort to validate the model. The successful development and validation of the proposed model will facilitate the discovery of more effective drugs for osteoarthritis. Furthermore, the research is likely applicable to the study of all chronic pain states and will help advance our understanding of the broad impact pain has on higher order mammals including humans. This grant proposes a new preclinical strategy for assessing pain and the effectiveness of analgesic drug candidates in rodents that is congruent with current methods of pain assessment in human and veterinary populations. This strategy will complement the more traditional procedures for assessing pain and antinociceptive activity, and help in the development of safer and more effective treatments for chronic pain.

描述（由申请人提供）：处方阿片类镇痛药和非甾体抗炎药是慢性疼痛的一线治疗方法。然而，不一致的治疗效果和/或副作用限制了它们的使用。开发更好的镇痛药需要预测和可靠的临床前（动物）疼痛模型。尽管疼痛通常与疼痛诱发行为（例如戒断反应）和疼痛抑制行为（例如进食、运动、运动等正常适应性行为的减少）相关，但目前的临床前疼痛模型几乎完全依赖于疼痛诱发行为。这种方法至少有两个限制。首先，尽管疼痛诱发行为的测定被认为可以预测许多急性疼痛状态，但它们可能缺乏作为慢性疼痛模型的临床相关性。为了支持这一点，临床医学（人类和兽医）中慢性疼痛的评估在很大程度上依赖于疼痛抑制行为的测量，以评估疼痛的存在和影响以及治疗的有效性。其次，药物不仅可以通过减少疼痛的感觉体验（真正的镇痛）来减少疼痛诱发的行为，还可以通过产生运动障碍来减少疼痛诱发的行为，从而导致“假阳性”效应。这项学术研究增强奖 (AREA) 申请的主要目标是通过开发和验证新的动物模型来解决这些局限性，这些模型可以通过测量啮齿类动物的疼痛抑制行为来评估临床前镇痛功效。该申请的第二个目标是帮助促进新 PI 作为独立科学家的职业生涯，并帮助进一步加强新英格兰大学的本科生研究环境。据推测，疼痛抑制行为模型可以捕获疼痛的临床重要方面，而使用疼痛诱发行为的标准分析可能会错过这些方面。还假设产生运动障碍的药物不会在此类模型中产生“假阳性”镇痛作用。为了支持这些假设，初步数据表明，标准亚急性伤害性刺激（腹腔注射乙酸）可以可靠地抑制运动活动，并且原型镇痛药物可以选择性地恢复疼痛抑制的运动活动（吗啡）。我将根据两个具体目标进一步验证和扩展这些发现：（1）评估骨关节炎引起的疼痛对运动活动和车轮运行的影响；（2）评估镇痛和非镇痛药物对观察到的疼痛抑制行为的影响。努力验证模型。该模型的成功开发和验证将有助于发现更有效的骨关节炎药物。此外，这项研究可能适用于所有慢性疼痛状态的研究，并将有助于加深我们对疼痛对包括人类在内的高级哺乳动物的广泛影响的理解。该资助提出了一种新的临床前策略，用于评估啮齿类动物的疼痛和候选镇痛药物的有效性，该策略与当前人类和兽医群体疼痛评估方法一致。该策略将补充评估疼痛和抗伤害活性的更传统程序，并有助于开发更安全、更有效的慢性疼痛治疗方法。