Distribution of NGF receptors in the enteric nervous system of the rat colon: Selective loss of NGF sensitivity following experimental colitis.

摘要

Nerve growth factor (NGF) acts on the two-receptor system of trkA and p75 to mediate neuroprotection and influence phenotype and function in the central and peripheral nervous systems, but the effects of NGF on the enteric nervous system (ENS) are virtually unknown. To establish a structural basis for enteric responsiveness to NGF and test the hypothesis that NGF is neuroprotective in the ENS, we studied the presence and distribution of NGF sensitive receptors in the myenteric neurons of the normal rat colon and those recovered from TNBS colitis. Immunocyrtochemistry on whole mounts showed that the two NGF receptors were abundantly present in the ENS, with 70.6 ± 5.0% of all neurons positive for trkA and 78.1 ± 2.3% for p75. Over 60% of the myenteric neurons expressed both receptors, evidence for high NGF sensitivity. TrkA was co-expressed with choline acetyltransferase (60.9 ± 0.8%), neuronal nitric oxide synthase (22.4 ± 0.5%) and calbindin (9.7 ± 1.0%), respective markers for excitatory, inhibitory and sensory neurons in the ENS, suggesting widespread potential for NGF action among the diverse enteric phenotypes. In rats recovered from TNBS colitis (day 35), this distribution was changed to 38.7 ± 6.4%, 29.8 ± 3.1%, and 9.6 ± 2.3%, respectively. Furthermore, only 38.4% of the myenteric neurons in day 35 animals expressed both receptors since on average, trkA positive neurons decreased from 23.6 ± 0.2 to 7.9 ± 0.3 neurons per ganglion (p 0.01), suggesting that NGF sensitive neurons are selectively targeted for death during severe colitis. It was concluded that the receptors for NGF are widely distributed among the diverse ENS phenotypes, and that NGF is not directly neuroprotective during inflammation. Moreover, enteric inflammation may lead to the loss or damage of a novel NGF mediated regulatory system.