Mueller-Tribbensee Sonja M, Karna Manoj, Khalil Mohammad, Neurath Markus F, Reeh Peter W, Engel Matthias A
Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany.
PLoS One. 2015 Jul 24;10(7):e0128242. doi: 10.1371/journal.pone.0128242. eCollection 2015.
Various transient receptor potential (TRP) channels in sensory neurons contribute to the transduction of mechanical stimuli in the colon. Recently, even the cold-sensing menthol receptor TRPM(melastatin)8 was suggested to be involved in murine colonic mechano-nociception.
To analyze the roles of TRPM8, TRPA1 and TRPV4 in distension-induced colonic nociception and pain, TRP-deficient mice and selective pharmacological blockers in wild-type mice (WT) were used. Visceromotor responses (VMR) to colorectal distension (CRD) in vivo were recorded and distension/pressure-induced CGRP release from the isolated murine colon ex vivo was measured by EIA.
Distension-induced colonic CGRP release was markedly reduced in TRPA1-/- and TRPV4-/- mice at 90/150 mmHg compared to WT. In TRPM8-deficient mice the reduction was only distinct at 150 mmHg. Exposure to selective pharmacological antagonists (HC030031, 100 μM; RN1734, 10 μM; AMTB, 10 μM) showed corresponding effects. The unselective TRP blocker ruthenium red (RR, 10 μM) was as efficient in inhibiting distension-induced CGRP release as the unselective antagonists of mechanogated DEG/ENaC (amiloride, 100 μM) and stretch-activated channels (gadolinium, 50 μM). VMR to CRD revealed prominent deficits over the whole pressure range (up to 90 mmHg) in TRPA1-/- and TRPV4-/- but not TRPM8-/- mice; the drug effects of the TRP antagonists were again highly consistent with the results from mice lacking the respective TRP receptor gene.
TRPA1 and TRPV4 mediate colonic distension pain and CGRP release and appear to govern a wide and congruent dynamic range of distensions. The role of TRPM8 seems to be confined to signaling extreme noxious distension, at least in the healthy colon.
感觉神经元中的各种瞬时受体电位（TRP）通道参与结肠机械刺激的转导。最近，甚至冷敏薄荷醇受体TRPM（褪黑素）8也被认为参与小鼠结肠机械性伤害感受。
为了分析TRPM8、TRPA1和TRPV4在扩张诱导的结肠伤害感受和疼痛中的作用，使用了TRP缺陷小鼠和野生型小鼠（WT）中的选择性药理阻断剂。记录体内对结直肠扩张（CRD）的内脏运动反应（VMR），并通过酶免疫分析（EIA）测量离体分离的小鼠结肠中扩张/压力诱导的降钙素基因相关肽（CGRP）释放。
与WT相比，在90/150 mmHg时，TRPA1-/-和TRPV4-/-小鼠中扩张诱导的结肠CGRP释放明显减少。在TRPM8缺陷小鼠中，仅在150 mmHg时减少明显。暴露于选择性药理拮抗剂（HC030031，100 μM；RN1734，10 μM；AMTB，10 μM）显示出相应的效果。非选择性TRP阻断剂钌红（RR，10 μM）在抑制扩张诱导的CGRP释放方面与机械门控DEG/ENaC（amiloride，100 μM）和牵张激活通道（钆，50 μM）的非选择性拮抗剂一样有效。对CRD的VMR显示，TRPA1-/-和TRPV4-/-小鼠在整个压力范围（高达90 mmHg）内有明显缺陷，但TRPM8-/-小鼠没有；TRP拮抗剂的药物作用再次与缺乏相应TRP受体基因的小鼠的结果高度一致。
TRPA1和TRPV4介导结肠扩张疼痛和CGRP释放，似乎控制着广泛且一致的扩张动态范围。TRPM8的作用似乎仅限于传递极端有害的扩张信号，至少在健康结肠中如此。
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