To investigate whether motoneurons react to signals deriving from target inflammation, we studied the facial motor nucleus after injections of phytohaemagglutinin in the snout of adult rats. This plant lectin is a tool widely used to induce proliferation and activation of T lymphocytes, and we observed marked lymphocyte infiltration in the injected facial muscles. Retrograde labelling of motoneurons was not detected after peripheral injections of fluorochrome-conjugated phytohaemagglutinin. Nitric oxide synthase, revealed by NADPH-diaphorase histochemistry, OX-42-immunoreactive microglia, and expression of the cell death repressor gene bcl-2, investigated with nonradioactive in situ hybridization and immunohistochemistry, were evaluated in the facial nucleus. Daily phytohaemagglutinin injections for 4 days, mimicking repeated muscle exposure to inflammatory stimuli, resulted after 2-day survival in NADPH-diaphorase induction in motoneurons and marked activation of the surrounding microglia. Quantitative image analysis of NADPH-diaphorase staining, and OX-42 immunoreactivity and microglial cell counts indicated highly significant increases with respect to saline-injected control cases. The occurrence of a neuroprotective retrograde response was evaluated monitoring bcl-2 expression. Following single phytohaemagglutinin administration, bcl-2 mRNA was significantly upregulated at 6 h in facial motoneurons and returned to basal levels at 24 h. Bcl-2 immunoreactivity was markedly upregulated at 24 h and was still significantly higher than in controls at 7 days, when concomitant NADPH-diaphorase induction in motoneurons and microglia activation was also observed. No degenerative features were observed in motoneurons after phytohaemagglutinin injections at the examined time-points. The data point out that local muscle inflammation retrogradely elicits gene activation in motoneurons and their microenvironment.