Title

Upper Respiratory Tract Trigeminal Nerve Responsiveness to Irritants is Highly Dynamic

Date of Completion

January 2011

Keywords

Health Sciences, Toxicology|Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Respiratory tract reflex responses are an important defense mechanism against noxious airborne materials. In the upper respiratory tract, sensory responsiveness to irritants is mediated by trigeminal nerves and is characterized by reduced breathing frequency due to braking at the onset of each expiration. This response was measured in the current study by plethysmography to provide a biomarker for sensory nerve activation. To determine if trigeminal responsiveness to irritants was increased through adenosine receptor-dependent pathways, sensory irritant responsiveness was measured in female C57Bl/6J mice immediately following subcutaneous injection of the adenosine precursor, adenosine 5'-monophosphate (AMP) or vehicle. Capsaicin (0.2 mg/m³), cyclohexanone (1500 ppm), and styrene (50 ppm) were used as prototypical irritants. All three irritants induced a mild sensory nerve response. This response was increased 2–4 fold in animals pretreated with AMP indicating sensitization of trigeminal nerves occurred. The AMP-sensitization was blocked by pretreatment with the broad acting adenosine receptor antagonist theophylline (20 mg/kg) and the adenosine A2 receptor antagonist 3,7-dimethy1-1-propargylxanthine (DMPX, 1 mg/kg). Additionally, the odorant ethyl sulfide was shown to enhance sensory nerve responsiveness to these irritants, which was also blocked by pretreatment with theophylline and DMPX. These results suggest adenosine A 2 receptor stimulation leads to trigeminal nerve sensitization and enhanced sensory irritant responsiveness.^ Menthol, a compound derived from peppermint, produces a cooling sensation which is thought to be mediated via neuronal TRPM8 channels. The effects on menthol on the trigeminal responsiveness induced by three irritants, acrolein, acetic acid, and cyclohexanone were examined. Menthol (16 ppm) completely abolished the sensory irritation response to acrolein (2 ppm), an agonist of TRPA1 irritant receptors, as did eucalyptol (460 ppm), another TRPM8 agonist. The effects of menthol and eucalyptol were not specific to acrolein, as they also attenuated sensory irritation responses to acetic acid (150 ppm) and cyclohexanone (1500 ppm), agonists that likely act via ASIC and TRPV1 receptors, respectively. These results indicate counter-irritation effects of menthol (and eucalyptol) are broad-based. Together, this research provides strong support that irritant responsiveness is highly dynamic, being enhanced by adenosine through A2 receptor pathways, and being diminished by menthol through TRPM8 receptor pathways. ^