tVNS Mitigates Neuroinflammation and Nociception in a Rodent LPS Endotoxemia Model

The vagus nerve plays a modulatory role in the gut-brain axis. Intestinal barrier dysfunction and lipopolysaccharide (LPS) leakage into the systemic circulation are associated with several conditions, such as irritable bowel syndrome (IBS) and migraine headache. This study investigates the impact of non-invasive transauricular vagus nerve stimulation (tVNS) on the neuroinflammatory markers and pain behavior following an acute LPS challenge. Sprague-Dawley rats (n = 28) were given LPS or vehicle and subjected to tVNS or sham intervention in an acute LPS animal model that mimics the systemic consequences of barrier dysfunction. Behaviors were evaluated at the baseline and 6 h later, complemented by testing the levels of serum and brain neuroinflammatory markers. Behavioral analyses revealed that LPS exposure reduced the time spent in the open arm, grooming duration, and periorbital mechanical pain thresholds, and increased freezing duration. The tVNS intervention reversed these behavioral changes induced by LPS. LPS administration triggered elevated serum levels of IL-6, CGRP, haptoglobin, and VE-cadherin. LPS also increased IL-1β, PAR-2, haptoglobin, CGRP, and HMGB1 levels in the brain tissue. The tVNS intervention reversed the effects observed in the brain, but it did not change the elevated levels of inflammatory molecules in the systemic circulation. tVNS has the potential to modulate neuroimmune interactions, with an early impact on the brain during LPS surge. tVNS may have potential therapeutic benefits in managing pain-related disorders associated with LPS endotoxemia.