Patients exposed to
organophosphate (OP) compounds demonstrate a
central apnea. The Kölliker-fuse nuclei (KF) are
cholinergic nuclei in the brainstem involved in central respiratory control. We hypothesize that exposure of the KF is both necessary and sufficient for OP induced
central apnea. We performed an animal study of acute OP exposure. Anesthetized and spontaneously breathing Wistar rats (n=24) were exposed to a lethal dose of
dichlorvos using three experimental models. Experiment 1 (n=8) involved systemic OP
poisoning using subcutaneous (SQ) 2,2-dichlorovinyl
dimethyl phosphate (
dichlorvos) at 100mg/kg or 3× LD50. Experiment 2 (n=8) involved isolated
poisoning of the KF using stereotactic microinjections of
dichlorvos (625μg in 50μl) into the KF. Experiment 3 (n=8) involved systemic OP
poisoning with isolated protection of the KF using SQ
dichlorvos (100mg/kg) and stereotactic microinjections of organophosphatase A (
OpdA), an
enzyme that degrades
dichlorvos. Respiratory and cardiovascular parameters were recorded continuously. Animals were followed post exposure for 1h or until death. There was no difference in
respiratory depression between animals with SQ
dichlorvos and those with
dichlorvos microinjected into the KF. Despite differences in amount of
dichlorvos (100mg/kg vs. 1.8mg/kg) and method of exposure (SQ vs. CNS microinjection), 10min following
dichlorvos both groups (SQ vs. microinjection respectively) demonstrated a similar percent decrease in respiratory rate (51.5 vs. 72.2), minute ventilation (49.2 vs. 68.8) and volume of expired gas (17.5 vs. 0.0). Animals with
OpdA exposure to the KF during systemic OP exposure demonstrated less
respiratory depression, compared to SQ
dichlorvos alone (p<0.04). No animals with SQ
dichlorvos survived past 25min post exposure, compared to 50% of animals with
OpdA exposure to the KF. In conclusion, exposure of the KF is sufficient but not necessary for OP induced
apnea. Protection of the KF during systemic OP exposure mitigates OP induced
apnea.