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Clinical studies have shown that neuromodulation therapies, such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS), reduce symptoms of chronic neuropathic and visceral pain. The neural mechanisms underlying SCS and TENS therapy are poorly understood. The present study was designed to compare the effects of SCS and TENS on spinal neuronal responses to noxious stimuli applied to the heart and esophagus. Direct stimulation of an intercostal nerve (ICNS) was used to simulate the effects of TENS. Extracellular potentials of left thoracic (T3) spinal neurons were recorded in pentobarbital anesthetized, paralyzed and ventilated male rats. SCS (50 Hz, 0.2 ms, 3-5 min) at a clinical relevant intensity (90% of motor threshold) was applied on the C1-C2 or C8-T1 ipsilateral spinal segments. Intercostal nerve stimulation (ICNS) at T3 spinal level was performed using the same parameters as SCS. Intrapericardial injection of bradykinin (IB, 10 μg/ml, 0.2 ml, 1 min) was employed as the noxious cardiac stimulus. Noxious thoracic esophageal distension (ED, 0.4 ml, 20 s) was produced by water inflation of a latex balloon. C1-C2 SCS suppressed excitatory responses of 16/22 T3 spinal neurons to IB and 25/30 neurons to ED. C8-T1 SCS suppressed excitatory responses of 10/15 spinal neurons to IB and 17/23 neurons to ED. ICNS suppressed excitatory responses of 9/12 spinal neurons to IB and 17/22 neurons to ED. These data showed that SCS and ICNS modulated excitatory responses of T3 spinal neurons to noxious stimulation of the heart and esophagus.Perspective: Neuromodulation of noxious cardiac and esophageal inputs onto thoracic spinal neurons by spinal cord and intercostal nerves stimulation observed in the present study may help account for therapeutic effects on thoracic visceral pain by activating the spinal dorsal column or somatic afferents.

While TRPV1, CGRP and NO are known to be localized in the same nerve terminals, our data indicate that SCS-induced vasodilation depends on CGRP release, but not NO release. NO, released from endothelial cells, may be associated with vascular smooth muscle relaxation and peripheral blood flow increase in response to SCS.

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Qin C, Farber JP, Foreman RD. Intraesophageal chemicals enhance responsiveness of upper thoracic spinal neurons to mechanical stimulation of esophagus in rats. Am J Physiol Gastrointest Liver Physiol 294: G708-G716, 2008. First published January 10, 2008 doi:10.1152/ajpgi.00477.2007.-Esophageal hypersensitivity is one of the most common causes of noncardiac chest pain in patients. In this study, we investigated whether exposure of the esophagus to acid and other chemical irritants affected activity of thoracic spinal neurons responding to esophageal distension (ED) in rats. Extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital sodium-anesthetized, -paralyzed, and -ventilated male rats. ED (0.2 or 0.4 ml, 20 s) was produced by water inflation of a latex balloon placed orally into the middle thoracic region of the esophagus. The chemicals were administered via a tube that was passed through the stomach and placed in the thoracic esophagus. To irritate the esophagus, 0.2 ml of HCl (0.01 N), bradykinin (10 g/ml), or capsaicin (10 g/ml) were injected for 1-2 min. Only neurons excited by ED were included in this study. Results showed that intraesophageal instillation of HCl, bradykinin, and capsaicin increased activity in 3/20 (15%), 7/25 (28%), and 9/20 (45%) neurons but enhanced excitatory responses to ED in 9/17 (53%), 8/15 (53%), and 7/11 (64%) of the remaining spinal neurons, respectively. Furthermore, intraesophageal chemicals were more likely to enhance the responsiveness of low-threshold neurons than high-threshold neurons to the esophageal mechanical stimulus. Normal saline (pH 7.4, 0.2 ml) or vehicle instilled in the esophagus did not significantly affect activity or ED responses of neurons. We conclude that enhanced responses of thoracic spinal neurons to ED by the chemically challenged esophagus may provide a possible pathophysiological basis for visceral hypersensitivity in patients with gastroesophageal reflux and/or esophagitis. visceral hypersensitivity; gastroesophageal reflux; noncardiac chest pain; esophagitis; heartburn ESOPHAGEAL PAIN AND/OR HYPERSENSITIVITY is one of the most common causes of noncardiac chest pain (NCCP). About 60% of such patients have gastroesophageal reflux disease (GERD). The typical symptoms of GERD are heartburn and/or acid regurgitation arising from the reflux of gastric acid. Surveys of the U.S. population suggest that 7-10% of adults experience these symptoms daily (21,23,24,31). Therefore, ϳ19 million people per year have to live with GERD, and as a result they experience a reduced quality of life. Among the various gastrointestinal diseases in the U.S. population, GERD creates the highest financial burden with the highest annual direct costs ($9.3 billion U.S. dollars) (44). Some patients with GERD have chronic complications such as various laryngeal and pulmonary disorders (22) and may develop esophagitis, Barrett's esophagus (precancerous lesion), or esophageal adenocarcinoma (5, 55). Despite the prevalence and clinical signi...

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