TRPA1 is a unique sensor of noxious stimuli and, hence, a potential drug target for analgesics. Here we show that the antinociceptive effects of spinal and systemic administration of acetaminophen (paracetamol) are lost in Trpa1 − / − mice. The electrophilic metabolites N-acetylp-benzoquinoneimine and p-benzoquinone, but not acetaminophen itself, activate mouse and human TRPA1. These metabolites also activate native TRPA1 and, as a consequence, reduce voltage-gated calcium and sodium currents in primary sensory neurons. The N-acetyl-pbenzoquinoneimine metabolite l-cysteinyl-S-acetaminophen was detected in the mouse spinal cord after systemic acetaminophen administration. In the hot-plate test, intrathecal administration of N-acetyl-p-benzoquinoneimine, p-benzoquinone and the electrophilic TRPA1 activator cinnamaldehyde produced antinociception that was lost in Trpa1 − / − mice. Intrathecal injection of a non-electrophilic cannabinoid, ∆ 9 -tetrahydrocannabiorcol, also produced TRPA1-dependent antinociception in this test. our study provides a molecular mechanism for the antinociceptive effect of acetaminophen and discloses spinal TRPA1 activation as a potential pharmacological strategy to alleviate pain.

Background: Mast cell-derived prostaglandin D 2 (PGD 2 ), may contribute to eosinophilic inflammation and mucus production in allergic asthma. Chemoattractant receptor homologous molecule expressed on TH 2 cells (CRTH2), a high affinity receptor for prostaglandin D 2 , mediates trafficking of TH 2 -cells, mast cells, and eosinophils to inflammatory sites, and has recently attracted interest as target for treatment of allergic airway diseases. The present study involving mice explores the specificity of CRTH2 antagonism of TM30089, which is structurally closely related to the dual TP/CRTH2 antagonist ramatroban, and compares the ability of ramatroban and TM30089 to inhibit asthma-like pathology.

The transient receptor potential vanilloid 4 (TRPV4) is a calcium permeable ion channel expressed in airway epithelial cells. Based on studies of cell lines and animals, TRPV4 has been suggested to play a role in the regulation of ciliary beat frequency (CBF). Whether the same is true for human ciliated epithelial cells is not known. Therefore, the aim was to examine the expression and function of TRPV4 in human native nasal epithelial cells. Expression of TRPV4 mRNA in nasal epithelial cells and in the cell lines BEAS2B and 16HBE was confirmed by quantitative real-time PCR. A marked apical TRPV4 immunoreactivity was observed in nasal epithelial cells using immunocytochemistry. Responses to pharmacological modulation of TRPV4 were assessed with calcium imaging and CBF measurements. The TRPV4 agonist GSK1016790A produced concentration-dependent calcium responses in TRPV4-expressing HEK293, BEAS2B and 16HBE cells, and the TRPV4 antagonist HC067047 caused a rightward shift of the GSK1016790A concentration-response curves. Nasal epithelial cells responded to the TRPV4 agonist GSK1016790A with increased intracellular calcium signals and increased CBF, followed by cessation of ciliary beating and cell death. These effects were prevented or inhibited by the TRPV4 antagonist HC067047, the TRP channel blocker ruthenium red or removal of extracellular calcium. We conclude that TRPV4 is expressed in human primary nasal epithelial cells and modulates epithelial calcium levels and CBF. Thus, TRPV4 may participate in mucociliary clearance and airway protection. However, exaggerated activation of TRPV4 may result in epithelial cell death.TRPV4 is a widely expressed TRP ion channel that functions as a calcium entry channel upon activation by diverse stimuli, including hypotonicity, innocuous heat, the synthetic ligand 4alpha-phorbol 12,13-didecanoate (4a-PDD), and endogenous metabolites of arachidonic acid [1][2][3][4]. In the human airways, TRPV4 expression has been shown in the epithelium of trachea and lung, including serous cells of submucosal glands [5]. TRPV4 expression has also been demonstrated in human sinus mucosa with increased levels in chronic rhinosinusitis [6].The airway epithelium is constantly exposed to fluctuations in extracellular osmolarity and mechanical respiratory efforts, and needs to be equipped with compensatory mechanisms. In line with this, expression of TRPV4 in a human bronchial epithelial cell line was suggested to detect hypotonic conditions and play a role in cellular volume regulation through potassium efflux due to activation of calcium-activated potassium channels [7,8]. TRPV4 activation has also been shown to decrease activity of aquaporin-5, a water channel located in the apical cell membrane, under hypotonic conditions in mouse lung epithelial cells and when expressed in human embryonal kidney (HEK) 293 cells [9]. Decreased aquaporin-5 activity in response to TRPV4-mediated calcium influx was proposed to enhance epithelial barrier function in response to hypotonic conditions or ...

Patients with allergic rhinitis feature an increased itch response to TRPV1 stimulation at seasonal allergen exposure. We suggest that this reflects part of the hyperresponsiveness that characterizes on-going allergic rhinitis. Intervention with the TRPV1-signalling pathway may offer potential treatments of this condition.