title: TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor.
abstract: 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.
authors.affiliation: Department of Neurology, Duke University, Durham, NC 27710, USA Pain Center and Department of Anesthesiology, Washington University, St Louis, MO 63110, USA Department of Neurobiology, Duke University, Durham, NC 27710, USA Department of Anesthesiology, Duke University, Durham, NC 27710, USA Clinics for Pain and Palliative Care, Duke University, Durham, NC 27710, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Patrick
authors.initials: P
authors.lastname: Kanju
authors.forename: Quan
authors.initials: Q
authors.lastname: Fang
authors.forename: Suk Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Puja K
authors.initials: PK
authors.lastname: Parekh
authors.forename: Whasil
authors.initials: W
authors.lastname: Lee
authors.forename: Carlene
authors.initials: C
authors.lastname: Moore
authors.forename: Daniel
authors.initials: D
authors.lastname: Brenner
authors.forename: Robert W
authors.initials: RW
authors.lastname: Gereau
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Liedtke
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005404:Fixatives / Q000633:toxicity*; D005557:Formaldehyde / Q000633:toxicity*; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced* / Q000473:pathology*; D011758:Pyrroles / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects; D043222:Ubiquitin Thiolesterase / Q000378:metabolism; D014738:Vibrissae / Q000187:drug effects / Q000294:innervation
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D005404:Fixatives; C573308:HC-067047; D009025:Morpholines; D009570:Nitriles; D011758:Pyrroles; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; C113580:U 0126; D005557:Formaldehyde; D048049:Extracellular Signal-Regulated MAP Kinases; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse
keywords: ERK; Formalin model; Formalin receptor; Irritant; MEK; TRPV4; Trigeminal ganglion; Trigeminal pain; Whisker pad