Department of Surgery, University of California, San Francisco, California, USA.
Am J Physiol Gastrointest Liver Physiol. 2010 Jan;298(1):G81-91. doi: 10.1152/ajpgi.00221.2009. Epub 2009 Oct 29.
The excitatory ion channel transient receptor potential ankyrin-1 (TRPA1) is prominently expressed by primary afferent neurons and is a mediator of inflammatory pain. Inflammatory agents can directly activate [e.g., hydroxynonenal (HNE), prostaglandin metabolites] or indirectly sensitize [e.g., agonists of protease-activated receptor (PAR(2))] TRPA1 to induce somatic pain and hyperalgesia. However, the contribution of TRPA1 to visceral pain is unknown. We investigated the role of TRPA1 in visceral hyperalgesia by measuring abdominal visceromotor responses (VMR) to colorectal distention (CRD) after intracolonic administration of TRPA1 agonists [mustard oil (MO), HNE], sensitizing agents [PAR(2) activating peptide (PAR(2)-AP)], and the inflammatory agent trinitrobenzene sulfonic acid (TNBS) in trpa1(+/+) and trpa1(-/-) mice. Sensory neurons innervating the colon, identified by retrograde tracing, coexpressed immunoreactive TRPA1, calcitonin gene-related peptide, and substance P, expressed TRPA1 mRNA and responded to MO with depolarizing currents. Intracolonic MO and HNE increased VMR to CRD and induced immunoreactive c-fos in spinal neurons in trpa1+/+ but not in trpa1(-/-) mice. Intracolonic PAR(2)-AP induced mechanical hyperalgesia in trpa1+/+ but not in trpa1(-/-) mice. TNBS-induced colitis increased in VMR to CRD and induced c-fos in spinal neurons in trpa1(+/+) but not in trpa1(-/-) mice. Thus TRPA1 is expressed by colonic primary afferent neurons. Direct activation of TRPA1 causes visceral hyperalgesia, and TRPA1 mediates PAR(2)-induced hyperalgesia. TRPA1 deletion markedly reduces colitis-induced mechanical hyperalgesia in the colon. Our results suggest that TRPA1 has a major role in visceral nociception and may be a therapeutic target for colonic inflammatory pain.
瞬时受体电位通道蛋白 ankyrin-1（TRPA1）是一种主要表达于初级传入神经元的兴奋性离子通道，是炎症性疼痛的介质。炎症介质可直接激活（如，4-羟基壬烯醛（HNE），前列腺素代谢物）或间接敏化（如，蛋白酶激活受体（PAR（2））的激动剂）TRPA1，以诱导躯体疼痛和痛觉过敏。然而，TRPA1 对内脏疼痛的贡献尚不清楚。我们通过测量 colitis 内给予 TRPA1 激动剂（芥末油（MO），HNE）、敏化剂（PAR（2）激活肽（PAR（2）-AP））和炎性试剂三硝基苯磺酸（TNBS）后 colorectum 扩张（CRD）引起的腹部内脏运动反应（VMR），研究了 TRPA1 在内脏痛觉过敏中的作用。TRPA1（+/+）和 TRPA1（-/-）小鼠。通过逆行追踪鉴定出支配结肠的感觉神经元，共表达免疫反应性 TRPA1、降钙素基因相关肽和 P 物质，表达 TRPA1mRNA，并对 MO 产生去极化电流反应。colitis 内的 MO 和 HNE 增加了对 CRD 的 VMR，并在 TRPA1（+/+）但不在 TRPA1（-/-）小鼠的脊髓神经元中诱导免疫反应性 c-fos。colitis 内的 PAR（2）-AP 诱导 TRPA1（+/+）但不在 TRPA1（-/-）小鼠的机械性痛觉过敏。TNBS 诱导的 colitis 增加了对 CRD 的 VMR，并在 TRPA1（+/+）但不在 TRPA1（-/-）小鼠的脊髓神经元中诱导 c-fos。因此，TRPA1 由 colonic 初级传入神经元表达。TRPA1 的直接激活导致内脏痛觉过敏，TRPA1 介导 PAR（2）诱导的痛觉过敏。TRPA1 缺失显著减少了 colitis 引起的结肠机械性痛觉过敏。我们的结果表明，TRPA1 在内脏伤害感受中起主要作用，可能是 colonic 炎症性疼痛的治疗靶点。
