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Background Distal esophageal acidification induces variable hyperalgesia in the non-acid exposed proximal esophagus. As the autonomic nervous system (ANS) modulates nociception, the aim was to determine whether autonomic reactivity to acid infusion predicted inter-individual differences in hyperalgesia. Methods In 25 healthy volunteers (18 women, age range 22-58, mean 36.5 years), using a double-blind, placebo-controlled crossover design, pain thresholds to electrical stimulation were determined in the proximal esophagus and foot (control) pre and post a 30-min distal esophageal infusion of 0.15 mol L−1 HCl or saline with autonomic monitoring. Sympathetic Cardiac Sympathetic Index and Skin Conductance Response and parasympathetic Cardiac Vagal Tone and Cardiac Sensitivity to Baroreflex measures were derived. Plasma cortisol was measured pre and post infusion as were anxiety and unpleasantness. Key Results Acid infusion reduced group pain threshold in the proximal esophagus (adjusted mean change −5.0 mA vs saline +3.4 mA, P < 0.001), and raised sympathetic measures (Cardiac Sympathetic Index, Skin Conduction Response) and cortisol levels, but reduced parasympathetic measures (cardiac vagal tone and cardiac sensitivity to Baroreflex) (all P < 0.05). Acid infusion also increased anxiety and unpleasantness scores (both P < 0.05). In 16 acid-sensitizers, the degree of hyperalgesia correlated with increasing heart rate ( r = −0.66, P = 0.005), and fall in cardiac vagal tone (r = 0.54, P = 0.03) and Cardiac Sensitivity to Baroreflex ( r = 0.54, P = 0.03). Conclusions & Inferences Acid-induced esophageal hyperalgesia correlated with reduced parasympathetic tone, suggesting that the parasympathetic nervous system may have anti hyperalgesic properties. Additional studies on the autonomic modulation of esophageal hyperalgesia are required. [ABSTRACT FROM AUTHOR]