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Trigeminal sensory neurons are responsible for sensory innervation to the nasal cavity and may release substance P (SP) upon exposure to inhaled irritants. In preliminary studies using rats exposed to silica dust, an increase in SP protein content and SP mRNA expression was demonstrated in trigeminal ganglia cell bodies. These findings suggested that silica dust initiated the nasal mucosa and activated sensory pathways in the upper airways. To identify neurons projecting to the nasal epithelium, rhodamine-labeled latex microspheres were instilled into the nasal cavity. Most neurons retrogradely labeled from the nasal cavity contained SP, suggesting the subpopulation innervating the nasal epithelium contained SP. Using this procedure, SP levels in specific nerve cell bodies projecting to the nasal spithelium could be evaluated. In the next experiment, rats were exposed to toluene diisocyanate (TDI) to examine neuronal reactions. An increased SP protein content and mRNA expression was observed in trigeminal cell bodies innervating the nasal epithelium 24 hours after intranasal instillation of 5 {dollar}\\mu{dollar}l of a 10% TDI solution. These findings suggested that TDI instillation activated specific SP sensory pathways from the nasal epithelium to the trigeminal ganglia. Experiments were then done to evaluate SP neuronal changes in response to inhaled TDI. The inhalation of 60-ppb TDI for 2 hrs caused a neuronal response followed by a recovery in both SP protein content and PPT mRNA expression in trigeminal cell bodies and in SP-IR nerve fibers of the nasal epithelium. An increase of SP protein content in epithelial nerve fibers was observed 12, 24 and 48 hrs after TDI exposure. The proportion of SP-containing cell bodies decreased at 24 hrs but was increased above controls at 48 and 72 hrs. Cell bodies expressing PPT mRNA increased above control levels at 24 and 48 hrs. All changes in protein content and message levels had recovered to control levels 96 hours after TDI inhalation. In conclusion, the TDI-induced SP changes in trigeminal neurons innervating the nasal epithelium may contribute to upper airway neurogenic inflammation by adjusting SP synthesis in the cell body and consequently regulating transmitter levels in the epithelial nerve terminals.