Silencing musculoskeletal pain: can we target spontaneously active neurons?

关节和肌肉的慢性疼痛是全球残疾的主要原因之一。我们的止痛药对很多人都不起作用，而且往往有可怕的副作用，就像阿片类药物成瘾一样。因此，我们迫切需要增加对慢性肌肉和关节疼痛原因的了解，以帮助我们开发更好的治疗方法。一个特别有前途的想法可能是瞄准从我们的身体（例如皮肤的触摸）到脊髓和大脑的感觉信息的神经。传递疼痛信息的感觉神经纤维本来是沉默的，除非我们伤害自己。然而，在某些情况下，如骨关节炎和类风湿性关节炎，它们会自发发出信号。这被认为是慢性疼痛的重要原因。事实上，它被认为是突发和自发性疼痛发作的一个可能原因，这对关节炎患者来说是非常具有破坏性的。尽管如此，我们对这些自发信号是如何产生的知之甚少。最重要的是，我们实际上并不知道哪种类型的外周神经纤维（有许多不同的类型）是主要负责的。如果没有这些信息，我们就无法开发出针对功能障碍的神经纤维的特定治疗方法。我们的建议旨在改变这一点。我们正在使用一种最近开发的成像技术，该技术使我们能够同时记录数百个神经纤维中的自发信号，而不是像以前那样必须逐个采样。有了这项技术和其他最近开发的工具，我们可以准确地确定哪些类型的神经纤维在关节炎动物模型中产生自发信号。然后，我们将使用化学工具来专门沉默自发神经纤维，并评估这是否会减少我们模型中的疼痛。在我们的工作结束时，我们将充分表征负责自发性疼痛的外周神经纤维。我们将与制药公司分享这些信息，以帮助他们努力开发数百万人迫切需要的改进的止痛药。

Chronic pain in joints and muscles is one of the leading causes of disability worldwide. The pain killers we have do not work for many people and often have terrible side effects, like addiction in the case of opioids. We therefore urgently need to increase our understanding of what causes chronic muscle and joint pain, to help us develop better treatments. One particularly promising idea could be to target the nerves that carry sensory information from our body (e.g. touch of the skin) to the spinal cord and brain. The sensory nerve fibres that transmit painful information are meant to be silent unless we injure ourselves. However, in conditions, like osteo- and rheumatoid arthritis, they are known to spontaneously emit signals. This is thought to be an important cause of chronic pain. Indeed, it is believed to be a likely reason for flare-ups and spontaneous pain attacks, which are extremely disruptive to individuals living with arthritis. Despite this, we understand very little about how these spontaneous signals arise. Most importantly, we do not actually know which type of peripheral nerve fibres (there are many different types) are primarily responsible. Without this information, we cannot develop specific treatments that are aimed just at the malfunctioning nerve fibres. Our proposal aims to change this. We are working with a recently developed imaging technique that allows us to record spontaneous signals in hundreds of nerve fibres at the same time, rather than having to sample them one-by-one - as was necessary previously. With this technique and other recently developed tools, we can determine exactly which types of nerve fibres develop spontaneous signals in animal models of arthritis. We will then use chemical tools to specifically silence the spontaneous nerve fibres and assess whether this reduces pain in our models. At the end of our work, we will have fully characterised the peripheral nerve fibres which are responsible for spontaneous pain. We will share this information with drug companies to help their efforts to develop the improved pain killers that millions of individuals so desperately need.