TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor.

Chen, Yong

Kanju, Patrick

Fang, Quan

Lee, Suk Hee

Parekh, Puja K

Lee, Whasil

Moore, Carlene

Brenner, Daniel

Gereau, Robert W

Wang, Fan

Liedtke, Wolfgang

United States

2016-10-21T02:56:57Z

2014-12

Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.

http://www.ncbi.nlm.nih.gov/pubmed/25281928

S0304-3959(14)00456-4

1872-6623

https://hdl.handle.net/10161/12970

eng

Ovid Technologies (Wolters Kluwer Health)

Pain

10.1016/j.pain.2014.09.033

ERK

Formalin model

Formalin receptor

Irritant

MEK

TRPV4

Trigeminal ganglion

Trigeminal pain

Whisker pad

Animals

Butadienes

Cells, Cultured

Disease Models, Animal

Enzyme Inhibitors

Extracellular Signal-Regulated MAP Kinases

Fixatives

Formaldehyde

Keratinocytes

Membrane Potentials

Mice

Mice, Inbred C57BL

Mice, Transgenic

Morpholines

Neurons

Nitriles

Pain

Pyrroles

TRPV Cation Channels

Trigeminal Ganglion

Ubiquitin Thiolesterase

Vibrissae

TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor.

Journal article

Moore, Carlene|0000-0002-1468-6408

Wang, Fan|0000-0003-2988-0614

Liedtke, Wolfgang|0000-0003-4166-5394

http://www.ncbi.nlm.nih.gov/pubmed/25281928

2662

2672

12

Anesthesiology

Basic Science Departments

Cell Biology

Clinical Science Departments

Duke

Duke Institute for Brain Sciences

Institutes and Provost's Academic Units

Neurobiology

Neurology

Neurology, Headache and Pain

School of Medicine

University Institutes and Centers

Published

155