Abstract
BackgroundThe transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells. It is activated by a variety of inflammatory mediators, such as methylglyoxal, formaldehyde and hydrogen sulphide. Since only few data are available about the role of TRPA1 in arthritis and related pain, we investigated its involvement in inflammation models of different mechanisms.MethodsChronic arthritis was induced by complete Freund’s adjuvant (CFA), knee osteoarthritis by monosodium iodoacetate (MIA) in TRPA1 knockout (KO) mice and C57Bl/6 wildtype mice. For comparison, carrageenan- and CFA-evoked acute paw and knee inflammatory changes were investigated. Thermonociception was determined on a hot plate, cold tolerance in icy water, mechanonociception by aesthesiometry, paw volume by plethysmometry, knee diameter by micrometry, weight distribution with incapacitance tester, neutrophil myeloperoxidase activity and vascular leakage by in vivo optical imaging, and histopathological alterations by semiquantitative scoring.ResultsCFA-induced chronic mechanical hypersensitivity, tibiotarsal joint swelling and histopathological alterations, as well as myeloperoxidase activity in the early phase (day 2), and vascular leakage in the later stage (day 7), were significantly reduced in TRPA1 KO mice. Heat and cold sensitivities did not change in this model. Although in TRPA1 KO animals MIA-evoked knee swelling and histopathological destruction were not altered, hypersensitivity and impaired weight bearing on the osteoarthritic limb were significantly decreased. In contrast, carrageenan- and CFA-induced acute inflammation and pain behaviours were not modified by TRPA1 deletion.ConclusionsTRPA1 has an important role in chronic arthritis/osteoarthritis and related pain behaviours in the mouse. Therefore, it might be a promising target for novel analgesic/anti-inflammatory drugs.
Highlights
The transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells
complete Freund’s adjuvant (CFA)-induced mechanical hypersensitivity and paw oedema are attenuated in TRPA1-deficient mice In WT animals an approximate 60 % decrease of the mechanonociceptive thresholds developed 1 day after the adjuvant injection, which gradually decreased to 40 % (4.88 ± 0.33 g) by the end of the study
Considerable hindpaw oedema developed in WT mice after the induction of arthritis reaching a maximal swelling of approximately 83 % on day 14
Summary
The transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable cation channel that is expressed on capsaicin-sensitive sensory neurons, endothelial and inflammatory cells. There are several exogenous irritants like mustard oil (allyl isothiocyanate: AITC) [29], cinnamaldehyde [30, 31], allicin [32, 33] and formalin [34] that are known to be potent agonists of TRPA1 Inflammatory mediators, such as bradykinin and serotonin, can sensitize this receptor and increase the responsiveness of the nerve endings [19, 35]. These findings suggest that TRPA1 may be involved in the development and maintenance of arthritic pain, but the precise mechanisms are still unknown
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