IntroductionFunctional chest pain of presumed esophageal origin (FCP) is a complex disorder whose central defining feature is chronic pain &, to date, has received limited attention in the literature. It has been postulated that a variable combination of genetic, psychological & physiological factors may contribute to its pathophysiology. AimsThe aim of this study was further characterize the pathophysiology of FCP by evaluating the serotonin transporter linked polymorphic region (5-HTTLPR) genotype & psychophysiological responses to visceral & somatic pain. Methods20 patients with Rome III defined FCP (9 male, mean age 38.7 years, range 21-59 years) & 20 healthy age, sex, ethnicity matched volunteers (9 male, mean 38.2 years, range 22-49) had personality traits assessed using validated questionnaires. Subjects had validated sympathetic (SNS) (skin conductance level) & parasympathetic (PNS) (cardiac vagal tone) parameters measured at baseline & continuously thereafter. Venous blood was taken for cortisol & 5-HTTLPR at baseline. Subjects received 7 somatic stimuli (nail bed pressure) to pain tolerance threshold (PTT), with a 2minute inter-stimulus interval (ISI), followed by 7 visceral stimuli (mid/distal esophageal distension) to PTT, with a 2-minute ISI. Blood was further sampled for serum cortisol after somatic & visceral pain. ResultsPatients had higher neuroticism (3.67 ±0.2 vs. 2 ±0.3, p<0.0001) state & trait anxiety (41.7 ±2.6 vs. 27.7 ±2.2, p=0.0007 & 43.5 ±2.4 vs. 28.4 ±8.5, p=0.009 respectively) & depression scores (4.82 ±0.6 vs. 1.9 ±0.3, p<0.0001) but lower extroversion scores (3 ±0.4 vs. 4.2 ±0.2, p=0.0002). At baseline, patients had higher serum cortisol (355nMol/L ±26 vs. 247nMol/L ±28, p=0.01), heart rate (75.9 beats per minute (bpm) ±4.7 vs. 67.2bpm ±1.7, p=0.04), SNS tone (4.2 μS ±0.9 vs. 2μS ±0.3, p= 0.04) but lower PNS tone (5.5u ±0.9 vs. 11.7u ±0.4, p=0.003). In response to pain, patients tolerated less somatic (48.4N ± 3.4 vs. 70.61N ± 3.6, p<0.0001) & visceral stimulus (30mls ±1.8 vs. 50.9mls ±6.9, p<0.0001) in the context of similar affective ratings of pain intensity & unpleasantness. After controlling for baseline, the pattern of cortisol increase was similar for both groups. Change in PNS tone increased to somatic & visceral pain in patients whereas in controls it decreased (53 %Δ/u ±18 vs. -14.1 %Δ/u ±5.2, p=0.002, 105 %Δ/u ±28 vs. -15.9 %Δ/u ±4.5, p=0.008). The presence of the short allele of the 5-HTTLPR was not different between the 2 groups (p=0.09). ConclusionsPatients with FCP display increased neuroticism & anxiety & this is reflected in higher SNS & cortisol tone at baseline. FCP patients display hyperalgesia with PNS activation in response to pain. These novel results provide preliminary evidence that psychological & physiological factors are involved in the pathophysiology of FCP.