ENDOGENOUS ANTI-OPIATE ANALGESIA SYSTEMS

内源性抗阿片类镇痛系统

基本信息

批准号：
3418505
负责人：
LINDA WATKINS
金额：
$ 15.63万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-29 至 1997-09-28
项目状态：
已结题

项目摘要

The CNS contains circuitry which can inhibit pain, thereby producing analgesia. This pain inhibitory circuitry can be activated by acute exposure of the organism to aversive/stressful environmental stimuli. Animals can also learn cues that predict that they will be exposed to aversive/stressful environmental stimuli, & become analgesic in response to these cues, called danger signals. Observations such as these led to the widely held view that the physiological function of such circuitry is to suppress pain during threatening situations, since pain perception at such a time would compromise efficient defense/escape behavior. Recent evidence strongly suggests the existence of neural circuitry with a function opposing that described above. That is this circuitry appears to specifically block analgesia, thereby producing anti-analgesia. To date, this blockade has been found only for opiate analgesias. Therefore it is possible that this is a specific "anti-opiate analgesia" system. A number of candidate anti-opiate analgesia neurotransmitters have been identified (e.g., CCK & FMRFamide). Injection of receptor agonists of such substances blocks opiate analgesias whereas receptor antagonists can markedly enhance the onset, peak effect & duration of a variety of opiate analgesic states. In addition to being able to learn danger signals, animals can learn cues that predict the non-occurrence of aversive events. For example, they can learn a light cue that signals that shock will not occur for a period of time. Thus, the light cue serves as a safety signal. It is now known that safety signals activate anti-opiate analgesia. That is, various opiate analgesias, including systemic & spinal morphine analgesias, are abolished by presentation of the safety signal. It is clear from these dramatic data that an understanding of endogenous anti-analgesia systems that function to oppose opiate analgesia may potentially provide novel approaches for the control of pain. The aim of the present proposal is to investigate the endogenous mechanisms underlying anti-analgesia. Dose-response studies will characterize the effect of the safety signal on opiate & non-opiate drug- & stress-induced analgesias, & will identify anti-analgesic substances mediating these effects. Time-response studies will characterize the development & duration of anti-analgesia. Generality of the safety signal effects will be examined by varying the stimulus used as the safety signal, by varying the conditioning parameters, & by varying the pain measures. By addressing well-defined, basic questions the proposed studies should provide major insights into the mechanisms underlying this newly discovered neural circuitry.

中枢神经系统包含可以抑制疼痛的电路，从而产生镇痛。这种疼痛抑制作用可以通过急性激活将生物体暴露于厌恶/压力的环境刺激中。动物还可以学习提示，以预测它们会暴露于厌恶/压力的环境刺激，并成为镇痛作用对于这些提示，称为危险信号。这样的观察导致这种电路的生理功能广泛认为是为了在威胁情况下抑制疼痛，因为疼痛感在这样的时候，将损害有效的防御/逃脱行为。最近的证据强烈表明存在神经回路与上述相反的功能。那就是这个电路出现特异性地阻断镇痛，从而产生抗扰动。到日期，仅针对阿片类镇痛而发现了这种封锁。所以这可能是一个特定的“抗核心镇痛”系统。许多候选抗焦虑镇痛神经递质已经已识别（例如CCK和FMRFAMIDE）。注射受体激动剂这样的物质阻止了阿片类镇痛，而受体拮抗剂可以明显增强了各种鸦片的发作，峰值效应和持续时间镇痛状态。除了能够学习危险信号外，动物还可以学习提示这可以预测厌恶事件的非发生。例如，他们可以学习一个信号，表明一段时间内不会发生冲击时间。因此，光提示是安全信号。现在已知该安全信号激活了抗焦点镇痛。也就是说，各种各样阿片类镇痛，包括全身和脊髓镇痛，是通过呈现安全信号废除。从这些可以清楚地理解内源性抗分析系统的戏剧性数据反对阿片类镇痛的功能可能有可能提供新颖的控制疼痛的方法。本提案的目的是研究内源性抗障碍的机制。剂量反应研究将表征安全信号对阿片类药物和非伴侣药物的影响＆压力引起的镇痛，并将识别抗动物物质调解这些效果。时间响应研究将表征反扰流的发展和持续时间。安全的一般性通过改变用作的刺激来检查信号效应安全信号，通过改变条件参数，并通过改变疼痛措施。通过解决定义明确的基本问题研究应提供有关此机制的主要见解新发现的神经回路。