Synaptic environment of nociceptive inputs to the spinal cord

每个人在人生的某个阶段都会受到疼痛的影响。通常，疼痛会随着根本原因的解决而自行消退。因此，受损的组织会愈合，或者我们会远离潜在的有害刺激，我们就不会感到疼痛了。然而，疼痛持续存在主要有两个原因：根本原因不能得到充分治疗，疼痛刺激继续；或者在最初的刺激消失后，疼痛会持续很长时间。这种持续的疼痛通常难以用普通止痛药缓解。因此，制药行业的一个主要目标是开发针对持续性疼痛的新药。这就要求我们彻底了解感知疼痛刺激的神经如何将信息传递到脊髓，然后再传递到大脑，在那里我们构建了对疼痛的有意识感知。各种各样的疼痛刺激，如组织损伤、有毒化学物质或极端温度，会被不同类型的神经检测到。每种神经类型都可以通过其特有的化学特征来识别。最近，我们发现这些神经中的一些可能并没有像大家想象的那样将信息传递给脊髓。这意味着必须有另一种方式将许多类型的疼痛刺激传递到脊髓。在这个项目中，我们将使用一套复杂的现代显微和电记录技术来找出这种替代机制是什么。我们的中心思想是，大多数类型的疼痛刺激同时激活两种感觉神经。然后，这些神经与脊髓中的特定神经细胞连接，然后将疼痛信息传递到大脑。我们的研究提出了一种新的机制来理解疼痛是如何从慢性疾病的急性防御反应发展而来的。反过来，这应该导致开发和测试新的镇痛药物的改进策略。

Pain affects everyone at some stage in their life. Usually, the pain subsides by itself as the underlying cause is resolved. Thus, the damaged tissue heals or we move away from a potentially injurious stimulus and we become free of pain. However, pain can persist for two main reasons: the underlying cause cannot be treated adequately and the painful stimulus continues; or the pain is maintained long after the primary stimulus has resolved. This ongoing pain often is resistant to alleviation by common analgesics. Therefore, a major aim of the pharmaceutical industry is the development of new drugs to target persistent pain. This requires a thorough understanding of how the nerves that detect painful stimuli transmit that information into the spinal cord, and then on to the brain, where we construct a conscious perception of the pain. Various kinds of painful stimuli, such as tissue damage, noxious chemicals, or extreme temperatures, are detected by different types of nerves. Each nerve type can be identified by its characteristic chemical profile. Recently, we found that some of these nerves probably do not transmit their messages to the spinal cord in the way everyone had thought. This means that there must be an alternative way for many types of painful stimuli to be transmitted into the spinal cord. In this project, we will use a sophisticated suite of modern microscopic and electrical recording techniques to find out what this alternative mechanism is. Our central idea is that most types of painful stimuli simultaneously activate two types of sensory nerves. These nerves then connect with specific nerve cells in the spinal cord before painful information is relayed to the brain. Our proposal suggests a new mechanism for understanding how pain can develop from being an acute defensive reaction to a chronic problem. In turn, this should lead to improved strategies for developing and testing new analgesic drugs.