Abstract
The cytokine tumor necrosis factorα (TNFα) is associated with a constellation of physiological and behavioral characteristics that follow in response to infection such as fever, fatigue, listlessness, loss of appetite, malaise, and tactile hypersensitivity. These responses are examples of central nervous system (CNS) functions modified by the activated immune system. Our studies have focused on the involvement of TNFα in CNS control of gastrointestinal function and "visceral malaise". We have demonstrated that TNFα can elicit gastric stasis in a dose-dependent fashion via its interaction with vago-vagal neurocircuitry in the brainstem. Sensory elements of the vago-vagal reflex circuit (i.e., neurons of the solitary tract [NST] and area postrema [AP]) are activated by exposure to TNFα, while the efferent elements (i.e., dorsal motor neurons of the vagus [DMN]) cause gastroinhibition. Transient exposure to low doses of TNFα cause potentiated (exaggerated) NST responses to stimulation. Subsequent studies suggest that TNFα presynaptically modulates the release of glutamate from primary afferents to the NST. Using immunohistochemical studies, we have observed the constitutive expression of the TNFR1 receptor on central vagal afferents and spinal trigeminal afferents in the medulla, as well as on cells and afferent fibers within the dorsal root ganglia and within laminae I and II of the dorsal horn throughout the spinal cord. The constitutive presence of these receptors on these afferents may explain why inflammatory or infectious processes that generate TNFα can disrupt gastrointestinal functions and cause tactile hypersensitivity. These receptors may also play a critical role in the chronic allodynia and hyper-reflexia observed after spinal cord injury or peripheral nerve damage.
Keywords: immune-neural interactions, gastric stasis, visceral malaise, hypersensitivity, potentiation, allodynia, illness behavior
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