Research Unit of Translational Neurogastroenterology, Institute for Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
Dig Dis. 2009;27 Suppl 1(0 1):24-30. doi: 10.1159/000268118. Epub 2010 Mar 4.
Inflammation is commonly associated with hyperalgesia. Ideally, this change should abate once inflammation is resolved, but this is not necessarily the case because phenotypic changes in the tissue can persist, as appears to be the case in post-infectious irritable bowel syndrome. Basically, all primary afferent neurons supplying the gut can be sensitized in response to pro-inflammatory mediators, and the mechanisms whereby hypersensitivity is initiated and maintained are, thus, of prime therapeutic interest.
There is a multitude of molecular nocisensors that can be responsible for the hypersensitivity of afferent neurons. These entities include: (i) receptors and sensors at the peripheral terminals of afferent neurons that are relevant to stimulus transduction, (ii) ion channels that govern the excitability and conduction properties of afferent neurons, and (iii) transmitters and transmitter receptors that mediate communication between primary afferents and second-order neurons in the spinal cord and brainstem. Persistent increases in the sensory gain may result from changes in the expression of transmitters, receptors or ion channels; changes in the subunit composition and biophysical properties of receptors and ion channels; or changes in the structure, connectivity and survival of afferent neurons. Particular therapeutic potential is attributed to targets that are selectively expressed by afferent neurons and whose number and function are altered in abdominal hypersensitivity.
Emerging targets of therapeutic relevance include distinct members of the transient receptor potential (TRP) channel family (TRPV1, TRPV4, TRPA1), acid-sensing ion channels, protease-activated receptors, corticotropin-releasing factor receptors and sensory neuron-specific sodium channels.
炎症通常与痛觉过敏有关。理想情况下，一旦炎症得到解决，这种变化就应该减轻，但情况并非总是如此，因为组织中的表型变化可能会持续存在，感染后肠易激综合征似乎就是这种情况。基本上，供应肠道的所有初级传入神经元都可以对促炎介质产生敏化，因此，引发和维持过敏反应的机制是主要的治疗关注点。
有许多分子伤害感受器可以导致传入神经元的过敏反应。这些实体包括：（i）与刺激转导相关的传入神经元外周末端的受体和传感器，（ii）调节传入神经元兴奋性和传导特性的离子通道，以及（iii）介导初级传入纤维和脊髓和脑干中的二级神经元之间通讯的递质和递质受体。感觉增益的持续增加可能是由于递质、受体或离子通道表达的变化、受体和离子通道的亚基组成和生物物理特性的变化、或传入神经元的结构、连接和存活的变化引起的。具有治疗潜力的特定靶点是选择性表达于传入神经元的靶点，其数量和功能在腹部过敏反应中发生改变。
有治疗相关性的新兴靶点包括瞬时受体电位 (TRP) 通道家族（TRPV1、TRPV4、TRPA1）、酸敏离子通道、蛋白酶激活受体、促皮质素释放因子受体和感觉神经元特异性钠通道的特定成员。
