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Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.

Mueller-Tribbensee SM, Karna M, Khalil M, Neurath MF, Reeh PW, Engel MA - PLoS ONE (2015)

Bottom Line: Recently, even the cold-sensing menthol receptor TRPM(melastatin)8 was suggested to be involved in murine colonic mechano-nociception.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).

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus

Representative pictures of murine visceromotor responses (VMR) to 90 mmHg-induced colorectal distension.Original EMG (in mV) recorded from the abdominal muscle in the different mouse strains during the 25 s of pressure/distension stimulation.
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pone.0128242.g004: Representative pictures of murine visceromotor responses (VMR) to 90 mmHg-induced colorectal distension.Original EMG (in mV) recorded from the abdominal muscle in the different mouse strains during the 25 s of pressure/distension stimulation.

Mentions: To scrutinize whether reduced colonic nociceptor activity as a result of TRPA1, TRPV4 or TRPM8 mutation/block was relevant for distension-induced colonic pain behavior, we chose the established model of measuring VMR to CRD. Integrated EMG activity from the abdominal muscles was measured to quantify the VMR. Baseline EMG-activity of WT and all knockout strains was about equal. The striking differences in EMG activity (in mV) between the different mouse strains are illustrated in Figs 4 and 5 showing representative EMGs at 90 mmHg. VMR to CRD was markedly reduced in TRPA1 and TRPV4 but not TRPM8 knockout mice at all pressure levels up to 90 mmHg (Fig 6A). Consistently, i.p. injection into WT mice of the selective TRPA1 antagonist HC030031 (10 mg/kg BW) or the TRPV4 antagonist RN1734 (1 mg/kg BW) led to reduced VMR which effect was relatively more prominent at the higher pressure levels (Fig 6B). The TRPM8 receptor antagonist AMTB (10 mg/kg BW) did not change VMR to CRD compared to vehicle-injected mice in the tested pressure range. Both, in vitro and in in vivo experiments did not show sex-specificity of any of the observed responses.


Differential Contribution of TRPA1, TRPV4 and TRPM8 to Colonic Nociception in Mice.

Mueller-Tribbensee SM, Karna M, Khalil M, Neurath MF, Reeh PW, Engel MA - PLoS ONE (2015)

Representative pictures of murine visceromotor responses (VMR) to 90 mmHg-induced colorectal distension.Original EMG (in mV) recorded from the abdominal muscle in the different mouse strains during the 25 s of pressure/distension stimulation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4514604&req=5

pone.0128242.g004: Representative pictures of murine visceromotor responses (VMR) to 90 mmHg-induced colorectal distension.Original EMG (in mV) recorded from the abdominal muscle in the different mouse strains during the 25 s of pressure/distension stimulation.
Mentions: To scrutinize whether reduced colonic nociceptor activity as a result of TRPA1, TRPV4 or TRPM8 mutation/block was relevant for distension-induced colonic pain behavior, we chose the established model of measuring VMR to CRD. Integrated EMG activity from the abdominal muscles was measured to quantify the VMR. Baseline EMG-activity of WT and all knockout strains was about equal. The striking differences in EMG activity (in mV) between the different mouse strains are illustrated in Figs 4 and 5 showing representative EMGs at 90 mmHg. VMR to CRD was markedly reduced in TRPA1 and TRPV4 but not TRPM8 knockout mice at all pressure levels up to 90 mmHg (Fig 6A). Consistently, i.p. injection into WT mice of the selective TRPA1 antagonist HC030031 (10 mg/kg BW) or the TRPV4 antagonist RN1734 (1 mg/kg BW) led to reduced VMR which effect was relatively more prominent at the higher pressure levels (Fig 6B). The TRPM8 receptor antagonist AMTB (10 mg/kg BW) did not change VMR to CRD compared to vehicle-injected mice in the tested pressure range. Both, in vitro and in in vivo experiments did not show sex-specificity of any of the observed responses.

Bottom Line: Recently, even the cold-sensing menthol receptor TRPM(melastatin)8 was suggested to be involved in murine colonic mechano-nociception.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).

View Article: PubMed Central - PubMed

Affiliation: Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

No MeSH data available.


Related in: MedlinePlus