The Effects of Morphine on Sensory and Motor Functions After A Spinal Cord Injury

描述（由申请人提供）： 脊髓损伤仅在美国就影响超过25万人，具有各种破坏性后果，包括肠、膀胱、性和肢体功能的丧失以及神经性疼痛。目前大量的研究都集中在寻找改善损伤后功能的方法上，然而令人惊讶的是，一线镇痛药对运动和感觉功能长期恢复的影响却知之甚少。阿片类药物是在受伤后不久给予的，并且被很大一部分脊柱受伤的人群使用，但我们不知道它们对功能恢复有什么影响。目前的建议旨在解决这一问题。我们将使用雄性Sprague-Dawley大鼠观察脊髓挫伤后重复吗啡暴露的功能后果。初步数据表明，即使是单剂量的吗啡也会对感觉功能（产生触觉异常性疼痛）和病变大小产生持久影响。我们还发现，无法控制的刺激会破坏感觉和运动功能，并与吗啡治疗相互作用，导致死亡率增加。拟议的实验将使用临床相关的延长吗啡治疗方案来扩展这项研究。使用广泛的行为测试，我们将比较给予单次注射吗啡、重复注射吗啡（0、2.5、5、10、20 mg/kg）或盐水3周的大鼠的运动和感觉恢复。由于吗啡治疗的后果可能在环境挑战的存在下最为明显，因此每种条件下的一半受试者将在损伤后1天接受30分钟的不可控制的刺激。将监测功能恢复6周。因此，拟议的研究将使用2（急性与延长吗啡）× 5（剂量）× 2（休克与非休克）的实验设计，以揭示吗啡的功能后果。假设是延长吗啡治疗会破坏恢复。这些影响在高剂量后和接受不可控刺激的受试者中可能最明显。这项初步研究将为许多未来的研究项目奠定基础，这些研究项目着眼于1）吗啡作用的分子机制，2）损伤变量（如病变大小）的影响，以及3）其他一线镇痛药（如NSAIDS，对乙酰氨基酚和加巴喷丁）对脊髓损伤后功能恢复的影响。

DESCRIPTION (provided by applicant): Spinal cord injury affects over a quarter of a million people in the United States alone, with a variety of devastating consequences including loss of bowel, bladder, sexual, and limb function, and neuropathic pain. Considerable research is now focused on finding ways to ameliorate the functional consequences of injury.Surprisingly, however, little is known about the consequences of first-line analgesics on the long-term recovery of motor and sensory function. Opiates are given soon after an injury and are used by a significant proportion of the spinally-injured population, but we do not know what impact they have on functional recovery. The current proposal aims to address this issue. We will look at the functional consequences of repeated morphine exposure after a spinal contusion injury using male, Sprague-Dawley rats. Preliminary data suggests that even a single dose of morphine can have a lasting effect on both sensory function (producing a tactile allodynia) and lesion size. We have also shown that uncontrollable stimulation undermines sensory and motor function, and interacts with morphine treatment, producing an increase in mortality. The proposed experiments will extend this research using a clinically relevant, extended morphine treament regime. Using a wide range of behavioral tests we will compare the motor and sensory recovery of rats given a single injection of morphine, repeated morphine injections (0, 2.5, 5,10, 20 mg/kg), or saline over a 3 week period. Because the consequences of morphine treatment may be most evident in the presence of an environmental challenge, half the subjects in each condition will receive 30 min of uncontrollable stimulation 1 day after injury. Functional recovery will be monitored for 6 weeks. The proposed studies, therefore, will use a 2 (acute vs extended morphine) x 5 (dose) x 2 (shock vs unshock) experimental design to elicidate the functional consequences of morphine. The hypothesis is that extended morphine treatment will undermine recovery. These effects may be most evident after a high dose and in subjects that receive uncontrollable stimulation. This initial study will lay the foundation for many future research projects looking at 1) the molecular mechanisms underlying the effects of morphine, 2) effects of injury variables such as lesion size, and 3) impacts of other first-line analgesics such as NSAIDS, acetaminophen, and gabapentin on the recovery of function after a spinal cord injury.