Defining a pain phenotype that is predictive of altered central pain processing in dogs with spontaneous osteoarthritis

直到最近，人们的疼痛被认为是一个单一的统一实体;无论潜在原因如何，个体经历的疼痛的性质都被认为是相似的。然而，这个概念现在受到了挑战，这当然符合每个人对组织损伤，创伤或手术引起的疼痛的独特体验。每种疾病引起的疼痛的性质和质量是不同的，反映了引起疼痛的感觉系统的潜在变化。例如，人们可能会表现出对温暖或寒冷刺激的敏感性的不同变化，反映了疼痛的不同潜在病因或机制。在人类中，这导致了疼痛的个性化治疗。现在，在人类中，可以识别与感觉处理中的不同变化相关的不同疼痛模式（称为疼痛表型），并使用特定药物靶向感觉处理中的这些潜在变化。这导致慢性疼痛患者的疼痛管理得到改善。目前这项提案的目的是将个性化疼痛治疗的概念从人转移到狗身上，并随后提高我们为患有慢性疼痛的狗提供充分疼痛缓解的能力。一个非常常见的原因慢性疼痛的狗是骨关节炎。我们目前假设所有患有骨关节炎的狗都遭受类似的疼痛，并对感觉刺激（如热和压力）表现出类似的敏感性改变。然而，在患有骨关节炎的人中，识别与不同感觉敏感性相关的不同类型的疼痛，并且这些不同的疼痛模式可能与感觉神经系统中的不同潜在变化相关。我们预测，考虑到狗和人的骨关节炎疾病之间的相似性，我们将能够在患有骨关节炎的狗中识别出相似的不同疼痛模式。我们将研究患有骨关节炎的宠物犬，通过与兽医联系招募。狗将受益于详细的临床评估，他们的骨关节炎与后续建议，优化他们的疼痛管理，潜在疼痛机制的一个主要问题是疼痛是否主要由周围神经系统感觉处理的变化引起（即在处理定位于疾病过程部位的感觉刺激时，在骨关节炎的情况下，这将是受影响的关节）或疼痛是否由外周（关节）和中枢神经系统（即脊髓和脑）的变化引起。一旦疼痛与外周和中枢神经系统的变化有关，它就变得更加难以有效地管理，并且还需要不同的疼痛管理策略，例如需要不同类型的止痛药物。我们将使用一个简单的，有效的实验范式，以区分是否都在感觉处理的外周或外周和中枢的变化，目前在个别狗骨关节炎。该测试将在麻醉的狗中进行，因此不知道。随后，在清醒的动物中，我们将绘制个体疼痛模式或疼痛表型，以使我们能够将疼痛机制与临床疼痛表达联系起来。这将通过测试对温暖、热量、寒冷和压力刺激的敏感性来实现。最终，我们希望兽医能够在他们的诊所检查患有骨关节炎的狗，并使用简单和非侵入性的测试来确定它们的疼痛表型，并使用这些信息来获得潜在疼痛机制的知识。这将允许兽医针对患者或个性化疼痛药物治疗，目的是改善疼痛管理和个体动物的终身福利。

Until very recently, pain in people was considered to be a single uniform entity; the nature of the pain experienced by an individual was considered to be similar regardless of the underlying cause. However this concept has now been challenged, which of course fits with everyone's own unique experience of pain resulting from tissue injury, trauma or surgery. The nature and quality of pain caused by each disease condition is different and reflects the underlying changes in the sensory system responsible for causing pain. For example, people may show differing changes in sensitivity to warm or cold stimuli, reflecting different underlying aetiologies or mechanisms of pain. In man this has led to personalized therapy for pain. It is now possible, in people, to identify distinct pain patterns (termed pain phenotype) that relate to distinct changes in sensory processing and target these underling changes in sensory processing with specific drugs. This has resulted in improved pain management in people in chronic pain. The aim of this current proposal is to translate the concept of personalized pain therapy from people to dogs and subsequently increase our capability to provide adequate pain relief to dogs suffering from chronic pain. A very common cause of chronic pain in dogs is osteoarthritis. We currently assume that all dogs with osteoarthritis suffer similarly from pain and show similar altered sensitivity to sensory stimuli such as heat and pressure. However, in people suffering from osteoarthritis, different types of pain associated with different sensory sensitivities are recognized, and these distinct pain patterns are likely associated with different underlying changes in the sensory nervous system. We predict, given the similarity between the disease of osteoarthritis in dogs and man, we will be able to identify similar distinct pain patterns in dogs suffering from osteoarthritis. We will study pet dogs with osteoarthritis, recruited through liaison with veterinary surgeons. The dogs will benefit from a detailed clinical assessment of their osteoarthritis with follow up advice about optimising their pain management, provided by European Specialists in canine osteoarthritis and animal pain management.A major discriminator in the underlying pain mechanisms is whether the pain results primarily from changes in sensory processing in the peripheral nervous system (i.e. in the processing of sensory stimuli localised to the site of the disease process, in the case of osteoarthritis this would be the affected joint) or whether pain is caused by changes in the periphery (the joint) and in the central nervous system (i.e. the spinal cord and brain). Once pain is associated with peripheral AND central nervous system changes it becomes much more difficult to manage effectively and also requires different pain management strategies, for example different types of pain killing drugs are necessary. We will use a simple, validated experimental paradigm to distinguish whether both peripheral OR peripheral AND central changes in sensory processing are present in individual dogs with osteoarthritis. This test will be carried in dogs that are anaesthetised and therefore unaware. Subsequently, in awake animals, we will map the individual pain pattern or pain phenotype to allow us to link pain mechanism with clinical pain expression. This will be achieved by testing sensitivities to warmth, heat, cold and pressure stimuli. Ultimately, we hope that a veterinary surgeon will be able to examine a dog with osteoarthritis in their clinic, and determine using simple and non-invasive tests, their pain phenotype, and use this information to derive knowledge of the underlying pain mechanisms. This will allow the veterinary surgeon to target or personalize pain medication to the patient, with the goal of improved pain management and the lifelong welfare of the individual animal.