RESUMEN
The current study was aimed at examining the role of cytochrome P450 (CYP450) activation and the electrophile-sensitive transient receptor potential ankyrin 1 receptor (TRPA1) in mediating the sensory irritation response to styrene and naphthalene. Toward this end, the sensory irritation to these vapors was measured in female C57Bl/6J mice during 15-min exposure via plethysmographic measurement of the duration of braking at the onset of each expiration. The sensory irritation response to 75 ppm styrene and 7 ppm naphthalene was diminished threefold or more in animals pretreated with the CYP450 inhibitor metyrapone, providing evidence of the role of metabolic activation in the response to these vapors. The sensory irritation response to styrene (75 ppm) and naphthalene (7.6 ppm) was virtually absent in TRPA1-/- knockout mice, indicating the critical role of this receptor in mediating the response. Thus, these results support the hypothesis that styrene and naphthalene vapors initiate the sensory irritation response through TRPA1 detection of their CYP450 metabolites.
Asunto(s)
Irritantes/toxicidad , Naftalenos/toxicidad , Mucosa Olfatoria/efectos de los fármacos , Estireno/toxicidad , Canales de Potencial de Receptor Transitorio/metabolismo , Animales , Biotransformación , Inhibidores Enzimáticos/farmacología , Femenino , Irritantes/farmacocinética , Metirapona/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Naftalenos/farmacocinética , Mucosa Olfatoria/metabolismo , Pletismografía , Respiración/efectos de los fármacos , Estireno/farmacocinética , Canal Catiónico TRPA1RESUMEN
The nose is innervated with both odor responsive olfactory (cranial nerve I) and irritant responsive trigeminal (cranial nerve V) nerves. The nature and extent of any interactions between these two nerves is poorly understood. The aim of the current study was to determine if two sulfur-containing malodorants, ethyl sulfide and t-butyl sulfide, modulated responsiveness to the trigeminal C fiber stimulant capsaicin using female C57Bl/6J mice as an experimental model. Cessation or marked slowing of flow at the onset of each expiration (termed braking) was used as a biomarker for trigeminal nerve stimulation. Aerosolized capsaicin solution (100 microg/ml) increased the time of braking from baseline levels of 8 ms to an average of 69 ms. At an exposure concentration of 100 ppm the malodorants induced only a minimal time of braking response (< 35 ms); the time of braking response in animals exposed to either malodorant plus capsaicin was 2.5-fold greater than in animals exposed to capsaicin alone (p < 0.01). In a subsequent experiment the time of breaking response to capsaicin was doubled (281 vs. 146 ms) by concomitant exposure to a no effect level of ethyl sulfide (11 ppm) and the modulation of capsaicin responsiveness was nearly abolished by inclusion of the adenosine antagonist theophylline in the aerosol formulation (time of braking 184 ms, p > or = 0.05 compared with capsaicin alone). These results suggest trigeminal nerve responsiveness is enhanced by exposure to malodorants through a theophylline-sensitive paracrine signaling pathway between olfactory and trigeminal nerves.
Asunto(s)
Capsaicina/toxicidad , Irritantes/toxicidad , Odorantes , Respiración/efectos de los fármacos , Sulfuros/toxicidad , Animales , Sinergismo Farmacológico , Femenino , Ratones , Ratones Endogámicos C57BL , Antagonistas de Receptores Purinérgicos P1 , Teofilina/farmacologíaRESUMEN
The molecular mechanisms through which sensory irritants stimulate nasal trigeminal nerves are poorly understood. The current study was aimed at evaluating the potential contribution of purinergic sensory transduction pathways in this process. Aerosols of 4-36 mM adenosine 5'-triphosphate (ATP) and adenosine both acted as sensory irritants. Large dose capsaicin pretreatment to induce degeneration of transient receptor potential vanilloid type-1 (TRPV1)-expressing C fibers greatly reduced, but did not abolish, the sensory irritation response to ATP aerosol and was without effect on the response to adenosine aerosol, indicating that ATP acts largely on capsaicin-sensitive (primarily C fibers) and adenosine acts on capsaicin-insensitive (primarily Adelta fibers) nerves. The response to adenosine was diminished by pretreatment with the broad-based adenosine receptor antagonist theophylline (20 mg/kg) and A1-selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (0.1 mg/kg), providing evidence that adenosine stimulates capsaicin-insensitive nerves via the A1 receptor. The sensory irritation responses to 275 ppm styrene and 110 ppm acetic acid vapors were significantly reduced by theophylline pretreatment suggesting a role for adenosine signaling pathways in activation of the sensory irritant response by these vapors. If sensory nerves are activated by mediators that are released from injured airway mucosal cells, then nasal sensory nerve activation may be a reflection of irritant-induced alterations in airway cell integrity.