Interactions Between the Brain Reward and Pain Systems.

描述（由申请人提供）：拟议研究的主要目的是研究大脑奖励系统与大脑疼痛系统的相互作用以及吗啡对这种相互作用的影响。在脑内植入两个刺激电极，一个在奖励部位，一个在伤害性部位，可以确定在奖励性脑刺激存在时的脑刺激逃避阈值（BSE），以及在伤害性刺激存在时的脑刺激奖励阈值（BSR）。这种相互作用可以帮助我们理解产生快乐的事件如何改变对痛苦的感知及其推论，导致痛苦的事件如何改变对快乐的感知。环境对疼痛调节产生影响的一个戏剧性例子是二战期间在意大利安齐奥建立滩头阵地的报道。许多伤员拒绝吗啡（75%），据报道，许多人都很兴奋。受伤意味着他们将被撤离，从而从这场战争中伤亡人数最多的战斗中活着逃脱。大脑刺激奖励程序允许直接激活大脑中负责日常愉悦事件的区域，例如食物、性、药物和最有可能的欣快感。在奖赏性脑刺激存在的情况下测量BSE阈值，可以研究大脑奖赏中心对疼痛感知的直接影响。另一个问题是，疼痛会改变大脑奖赏区域的敏感度吗？有疼痛的门诊病人，在不受控制的环境中使用处方阿片类药物，可能比没有疼痛的人暴露在相同的阿片类药物下更容易上瘾。因此，疼痛本身可能增加吗啡的奖励价值，促进阿片类药物成瘾。具体的实验将在大鼠身上进行，在每只动物身上手术植入两个电极，一个在奖励部位（内侧前脑束），另一个在疼痛部位（中脑网状结构）。除了确定奖励性脑刺激对刺激脑疼痛通路引起的疼痛感知的影响外，还将对奖励性脑刺激对两种外周疼痛刺激的影响进行实验。这包括对热刺激的反射性尾巴退缩（脊柱）和对伤害性足电击的工具性逃避（脊柱上）。在所有的实验中，阈值将使用经典极限法的修正来确定。公共卫生相关性：拟议的实验旨在确定大脑中与快乐相关的部分的激活是否会改变对疼痛的感知，以及这种激活是否会增强吗啡的镇痛作用。该研究的第二个方面将确定疼痛的存在是否通过使吗啡的效果更愉快而促进成瘾的发展。有可能这些发现将有助于开发更好的止痛剂，减少成瘾。

DESCRIPTION (provided by applicant): The major objective of the proposed research is to study the interaction of the brain reward system with the brain pain system and the effects of morphine on this interaction. The intracerebral implanting of two stimulating electrodes, one in a reward site and one in a nociceptive site allows the determination of the brain stimulation escape threshold (BSE) in the presence of rewarding brain stimulation as well as the determination of the brain stimulation reward threshold (BSR) in the presence of nociceptive stimulation. This interaction should help us understand how events that produce pleasure may alter the perception of pain and the corollary, how events that cause pain may alter the perception of pleasure. A dramatic example of the environment causing an impact on the modulation of pain was the report of the WWII establishment of a beachhead at Anzio in Italy. Many of the wounded refused morphine (75%) and it was reported that many were euphoric. The wound meant they would be evacuated and thus escape alive from one of the highest casualty battles of the war. The brain stimulation reward procedure allows a direct activation of that area of the brain that subserves usual pleasurable events, e.g., food, sex, drugs and most likely euphoria. Measurement of the BSE threshold in the presence of rewarding brain stimulation allows a study of the direct effect of the brain reward centers on the perception of pain. The reciprocal question, does pain change the sensitivity of a brain reward site? Out-patients in pain, who are not in a controlled environment and are using prescription opiates, may be a greater risk for addiction than the person without pain exposed to the same opiates. Thus, the pain itself may increase the rewarding value of morphine facilitating opiate addiction. The specific experiments will be carried out in rats in which two electrodes are surgically implanted in each animal, one in a reward site (the medial forebrain bundle) and the other in a pain site (mesencephalic reticular formation). In addition to determining the effect of rewarding brain stimulation on the perception of pain caused by stimulating a brain pain pathway, experiments will be conducted on the effect of rewarding brain stimulation on two types of peripheral pain stimulation. These involve a reflexive tail withdrawal to a heat stimulus (spinal) and instrumental escape from nociceptive foot shock (supra spinal). In all of the experiments thresholds will be determined using a modification of the classic method of limits. PUBLIC HEALTH RELEVANCE: The proposed experiments are designed to determine if activation of those parts of the brain that are related to pleasure will alter the perception of pain and whether such activation will enhance the analgesic effects of morphine. A second aspect of the research will determine if the presence of pain contributes to the development of addiction by making the effect of morphine more pleasurable. It is possible that such findings will contribute to the development of better analgesics that are less addicting.