Effect of pantoprazole in older patients with erosive esophagitis.

Several studies suggest that older adults with gastroesophageal reflux disease (GERD) are more likely to develop complications, including erosive esophagitis, but it is unclear whether erosive esophagitis is more difficult to treat in older patients. The purpose of this study was to determine if adults > or = 65 years with erosive esophagitis are more difficult to treat than younger adults. The study was a post hoc analysis of two double-blind, randomized, multicenter trials of patients with erosive esophagitis. Patients received pantoprazole 40 mg once daily, nizatidine 150 mg twice daily or placebo. Patients were evaluated for endoscopic healing at 4 and 8 weeks. Patients recorded typical reflux symptoms using a daily diary to note presence or absence of symptoms. Results showed that 44, 13 and 11 patients > or = 65 years and 210, 69, and 71 patients < 65 received pantoprazole 40 mg daily, nizatidine 150 mg twice daily, or placebo, respectively. Eighty-six percent (86%[76%, 97% CI]) of older and 83% (78%, 88% CI) of younger pantoprazole-treated patients were healed at 8 weeks; 46% (19%, 73% CI) and 35% (24%, 46% CI) of nizatidine-treated and 27% (1%, 54% CI) and 34% (23%, 45% CI) of placebo-treated were healed at 8 weeks. Median time to persistent absence of GERD-related symptoms was similar for older and younger patients treated with pantoprazole. We conclude that older patients with erosive esophagitis do not appear to have more difficult-to-treat disease. Erosive esophagitis is effectively healed and GERD symptoms are controlled in older patients using pantoprazole 40 mg daily.

Heme oxygenase activity in the internal anal sphincter: effects of nonadrenergic, noncholinergic nerve stimulation.

BACKGROUND & AIMS: To date, the exact role of carbon monoxide (CO) in the nonadrenergic, noncholinergic (NANC) relaxation is not known. This is partly related to the lack of an appropriate method to measure heme oxygenase (HO) activity in the gastrointestinal tissues. METHODS: HO activity of the opossum internal anal sphincter (IAS) smooth muscle was determined using a newly developed assay system that used radiolabeled hemin as a substrate. Enzyme activity of the IAS tissues was measured in the basal state, after electric field stimulation (EFS), ganglionic stimulant dimethyl diphenyl piperazinium iodide (DMPP), and neuropeptide vasoactive intestinal polypeptide (VIP). The presence and localization of HO was examined by Western blot analysis and immunocytochemistry. RESULTS: NANC nerve stimulation of the IAS smooth muscle by EFS (0.25-5 Hz), DMPP, and VIP caused a significant increase in the HO activity of the IAS. The increase in HO activity by EFS was inhibited by the HO inhibitor Tin protoporphyrin (1 x 10(-4) mol/L). Both HO-1 and HO-2 were present in the IAS tissue extracts, and both enzymes were localized in the neurons of the myenteric plexus. The method for HO activity determination used in the present study was found to be reliable and reproducible. CONCLUSIONS: The data suggest that the HO pathway may have a role in neurally mediated relaxation of the IAS. The exact site of involvement and the source of HO activity, however, remains to be determined.

Heme oxygenase-2 distribution in anorectum: colocalization with neuronal nitric oxide synthase.

Recent investigations have suggested carbon monoxide (CO) as a putative messenger molecule. Although several studies have implicated the heme oxygenase (HO) pathway, responsible for the endogenous production of CO, in the neuromodulatory control of the internal anal sphincter (IAS), its exact role is not known. Nitric oxide, produced by neuronal nitric oxide synthase (nNOS) of myenteric neurons, is an important inhibitory neural messenger molecule mediating nonadrenergic noncholinergic (NANC) relaxation of the IAS. The present studies were undertaken to investigate in detail the presence and coexistence of heme oxygenase-2 (HO-2) with nNOS in the opossum anorectum. In perfusion-fixed, frozen-sectioned tissue, HO-2 immunoreactive (IR) and nNOS IR nerves were identified using immunocytochemistry. Ganglia containing HO-2 IR neuronal cell bodies were present in the myenteric and submucosal plexuses throughout the entire anorectum. Colocalization of HO-2 IR and nNOS IR was nearly 100% in the IAS and decreased proximally from the anal verge. In the rectum, colocalization of HO-2 IR and nNOS IR was approximately 70%. Additional confocal microscopy studies using c-Kit staining demonstrated the localization of HO-2 IR and nNOS IR in interstitial cells of Cajal (ICC) of the anorectum. From the high rate of colocalization of HO-2 IR and nNOS IR in the IAS as well as the localization of HO-2 IR and nNOS IR in ICC in conjunction with earlier studies of the HO pathway, we speculate an interaction between HO and NOS pathways in the NANC inhibitory neurotransmission of the IAS and rectum.

Renal type I inositol 1,4,5-trisphosphate receptor is reduced in streptozotocin-induced diabetic rats and mice.

The mechanisms underlying glomerular hypertrophy and hyperfiltration in diabetes remain unclear. We have previously demonstrated that the cytokine transforming growth factor-beta1 (TGF-beta1) is increased in early diabetic kidney disease and TGF-beta1 inhibits the expression of the inositol 1,4,5-trisphosphate (IP3)-gated calcium channel, the type I IP3 receptor (IP3R), in mesangial cells. To test the hypothesis that reduced type I IP3R may be important in diabetic kidney disease, we evaluated type I IP3R expression in the kidney of streptozotocin-induced diabetic rats and mice. Two-week-old diabetic rats have decreased renal type I IP3R protein and mRNA levels. Immunostaining of normal rat kidney demonstrated presence of type I IP3R in glomerular and vascular smooth muscle cells, whereas diabetic rats had reduced staining in both compartments. Reduction of type I IP3R also occurred in parallel with renal hypertrophy, increased creatinine clearance, and increased renal TGF-beta1 expression in the diabetic rats. Two-week-old diabetic mice also had reduced renal type I IP3R protein and mRNA expression in association with renal hypertrophy and increased TGF-beta1 mRNA expression. These findings demonstrate that there is reduced type I IP3R in glomerular and vascular smooth muscle cells in the diabetic kidney, which may contribute to the altered renal vasoregulation and renal hypertrophy of diabetes.

Clinical value of esophageal motility testing.

Esophageal motility testing is the method of choice in evaluating esophageal motor disorders. Some physicians, however, question the clinical utility of esophageal motility testing, since the results are often normal in symptomatic patients. The clinical utility of esophageal motility testing is reviewed for patients with a complaint of noncardiac chest pain, dysphagia or symptoms of gastroesophageal reflux disease. Esophageal motility testing is particularly useful for evaluating patients with dysphagia, but less so for gastroesophageal reflux disease patients, and has little clinical utility in patients with noncardiac chest pain.

Solitarial premotor neuron projections to the rat esophagus and pharynx: implications for control of swallowing.

BACKGROUND & AIMS: The buccopharyngeal and esophageal phases of swallowing are controlled by distinct networks of premotor neurons localized in the nucleus tractus solitarius. The neuronal circuitry coordinating the two phases was investigated using a combination of central and peripheral tracing techniques. METHODS: Using pseudorabies virus, a transsynaptic tracer, in anesthetized rats, third-order esophageal neurons (neurons projecting to premotor neurons) were identified. In a separate protocol that combined transsynaptic and retrograde fluorescent tracing, third-order esophageal neurons projecting to pharyngeal motoneurons (buccopharyngeal premotor neurons) were then identified. RESULTS: Third-order esophageal neurons were identified in the interstitial and intermediate subnuclei of the nucleus tractus solitarius and in other medullary, pontine, midbrain, and forebrain nuclei. A subpopulation of these neurons (double labeled) in the interstitial and intermediate subnuclei were found to project to pharyngeal motoneurons (buccopharyngeal premotor neurons) and to be linked synaptically to esophageal premotor neurons. CONCLUSIONS: The synaptic link between buccopharyngeal and esophageal premotor neurons provides an anatomic pathway for the central initiation of esophageal peristalsis and its coordination with the pharyngeal phase of swallowing. This neural circuitry within the nucleus tractus solitarius is consistent with a complex central control mechanism for the swallowing motor sequence that can function independently of afferent feedback.

Leptin receptors in the adrenal medulla of the rat.

Leptin is the protein product of the recently cloned obesity gene. Leptin receptor mRNA is found in a number of central and peripheral locations. The hypothalamus is a presumed site of action. However, little is known about the specific locations of the receptor in peripheral organs. Epinephrine has potent anorectic effects and can cause weight loss by a variety of mechanisms. Excretion of epinephrine is reduced in the ob/ob mouse, which lacks leptin, suggesting an effect by leptin on the adrenal medulla. In the current study, the presence of the leptin receptor was identified on epinephrine-secreting cells in the adrenal medulla. Immunohistochemical studies found dense leptin receptor-like immunoreactivity in the adrenal medulla with no labeling in the adrenal cortex. Double immunofluorescent labeling confirmed that the leptin receptor was present on cells that were phenylethanolamine N-methyltransferase-like immunoreactive and therefore were epinephrine-secreting cells. Leptin receptor mRNA in the adrenal medulla was detected by reverse transcriptase-polymerase chain reaction, with the majority of the mRNA coding for the short isoform (Ob-Ra) of the receptor. Finally, autoradiography was performed using 125I-labeled leptin; specific binding was found in the adrenal medulla, with no specific binding in the adrenal cortex. These results suggest that leptin may have a direct effect on epinephrine-secreting cells in the adrenal medulla. Epinephrine may play a role in mediating the effects of leptin to reduce body weight.

Ultrastructure of bombesin-like immunoreactive nerve terminals in the nucleus of the solitary tract and the dorsal motor nucleus.

Bombesin (gastrin-releasing peptide 14-27) inhibits gastric function and feeding when microinjected into the nucleus of the solitary tract (NTS)/dorsal motor nucleus of the vagus (DMV) complex. We performed a preembedding immunoelectron microscopic study in rats to describe the bombesin containing nerve terminals and to characterize their postsynaptic structures. 228 bombesin-L1 nerve terminals which made synaptic contacts in the NTS/DMV complex were studied. Labeling was heaviest over dense core vesicles and lighter over small clear vesicles. The dense core vesicles were typically located along the plasmalemma away from the synaptic face, a finding that is typical of neuropeptide containing nerve terminals. The postsynaptic structures were most often medium sized dendrites (56%) and small sized dendrites (27%), with similar percentages in the NTS and DMV. In the DMV, synapses on cell bodies (8%) were more frequent than in the NTS (1%). In the NTS, synapses on dendritic spines (10%) were more frequent than in the DMV (4%). Only a single axo-axonal contact was identified. These findings add to the increasing body of evidence that bombesin is a neurotransmitter/neuromodulator in the NTS/DMV complex. Bombesin rarely makes presynaptic (axo-axonal) contacts that might inhibit the release of excitatory neurotransmitters, but rather makes postsynaptic contacts potentially effecting vagal motoneurons.

Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance.

BACKGROUND: A receptor for leptin has been cloned from the choroid plexus, the site of cerebrospinal-fluid (CSF) production and the location of the blood/cerebrospinal-fluid barrier. Thus, this receptor might serve as a transporter for leptin. We have studied leptin concentrations in serum and (CSF). METHODS AND FINDINGS: We demonstrated by radioimmunoassay and western blot the presence of leptin in human CSF. We then measured leptin in CSF and serum in 31 individuals with a wide range of bodyweight. Mean serum leptin was 318% higher in 8 obese (40.2 [SE 8.6] ng/mL) than in 23 lean individuals (9.6 [1.5] ng/mL, p < 0.0005). However, the CSF leptin concentration in obese individuals (0.337 [0.04] ng/mL) was only 30% higher than in lean people (0.259 [0.26] ng/mL, p < 0.1). Consequently, the leptin CSF/serum ratio in lean individuals (0.047 [0.010]) was 4.3-fold higher than that in obese individuals (0.011 [0.002], p < 0.05). The relation between CSF leptin and serum leptin was best described by a logarithmic function (r = 0 x 52, p < 0.01). INTERPRETATION: Our data suggest that leptin enters the brain by a saturable transport system. The capacity of leptin transport is lower in obese individuals, and may provide a mechanism for leptin resistance.

Distribution of bombesin-like immunoreactivity in the nucleus of the solitary tract and dorsal motor nucleus of the rat and human: colocalization with tyrosine hydroxylase.

Bombesin is a peptide neurotransmitter/neuromodulator with important autonomic and behavioral effects that are mediated, at least in part, by bombesin-containing neurons and nerve terminals in the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus (DMV). The distribution of bombesin-like immunoreactive nerve terminals/fibers and cell bodies in relation to a viscerotopically relevant subnuclear map of this region was studied by using an immunoperoxidase technique. In the rat, bombesin fiber/terminal staining was heavy in an area that included the medial subnucleus of the NTS and the DMV over their full rostral-caudal extent. Distinctly void of staining were the gelatinous, central, and rostral commissural subnuclei and the periventricular area of the NTS, regions to which gastric, esophageal, cecal, and colonic primary afferents preferentially project. The caudal commissural and dorsal subnuclei had light bombesin fiber/terminal staining, as did the intermediate, interstitial, ventral, and ventrolateral subnuclei. With colchicine pretreatment, numerous cell bodies were stained in the medial and dorsal subnuclei, with fewer neurons in the caudal commissural, intermediate, interstitial, ventral, and ventrolateral subnuclei. Bombesin-like immunoreactive neurons were found in numerous other areas of the brain, including the ventrolateral medulla, the parabrachial nucleus, and the medial geniculate body. In the human NTS/DMV complex, the distribution of bombesin fiber/terminal staining was very similar to the rat. In addition, occasional bombesin-like immunoreactive neurons were labeled in a number of subnuclei, with clusters of neurons labeled in the dorsal and ventrolateral subnuclei. Double immunofluorescence studies in rat demonstrated that bombesin colocalizes with tyrosine hydroxylase in neurons in the dorsal subnucleus of the NTS. Bombesin does not colocalize with tyrosine hydroxylase in any other location in the brain. In conclusion, the distribution of bombesin in the NTS adheres to a viscerotopically relevant map. This is the anatomical substrate for the effects of bombesin on gastrointestinal function and satiety and its likely role in concluding a meal. The anatomic similarities between human and rat suggest that bombesin has similar functions in the visceral neuraxis of these two species. Bombesin coexists with catecholamines in neurons in the dorsal subnucleus, which likely mediate, in part, the cardiovascular effects of bombesin.

Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice.

The obese gene product, leptin, is synthesized in adipose tissue and is a circulating factor regulating body weight. To identify the location of leptin receptors in the brain we have performed an autoradiographic study of the binding of [(125)I]leptin to frozen sections of mouse brain. Dense specific binding of [(125)I]leptin was found only in the choroid plexus which is located in the dorsal part of the third ventricle and lateral ventricles. Specific binding of [(125)I]leptin was found the ob/ob and db/db mice. These findings further our understanding of the sites and mechanism of action of leptin on brain centers regulating body weight.

Colocalization of NADPH-diaphorase staining and VIP immunoreactivity in neurons in opossum internal anal sphincter.

Nitric oxide and vasoactive intestinal polypeptide (VIP) are important inhibitory neurotransmitters mediating relaxation of the internal anal sphincter. The location and coexistence of these two neurotransmitters in the internal anal sphincter has not been examined. We performed a double-labeling study to examine the coexistence of nitric oxide synthase and VIP in the opossum internal anal sphincter using the NADPH-diaphorase technique which is a histochemical stain for nitric oxide synthase. In perfusion-fixed, frozen-sectioned tissue, VIP-immunoreactive neurons were labeled using immunofluorescence histochemistry. After photographing the VIP-immunoreactive neurons, nitric oxide synthase was labeled using the NADPH-diaphorase technique. Ganglia containing neuronal cell bodies were present in the myenteric plexus for the entire extent of the internal anal sphincter. VIP-immunoreactive and NADPH-diaphorase-positive neurons were present in ganglia in the myenteric as well as the submucosal plexuses. Most of the VIP-immunoreactive neurons were also NADPH-diaphorase positive. VIP and nitric oxide synthase are present and frequently coexist in neurons in the internal anal sphincter of the opossum. These neurons may be an important source of inhibitory innervation mediating the rectoanal reflex-induced relaxation of the sphincter. The demonstration of the coexistence of these two neurotransmitters will be of fundamental importance in unraveling their relationship and interaction in the internal anal sphincter as well as other systems.

Irritable bowel syndrome. Managing the patient with abdominal pain and altered bowel habits.

Irritable bowel syndrome is a common complex of syndromes thought to be generated by a motility or sensory disturbance of the gastrointestinal tract. It is a frequent cause of chronic abdominal pain and altered bowel habits. Patients who seek medical attention for irritable bowel syndrome often do so because of psychosocial factors. Therapy remains largely empirical, directed toward the relief of symptoms in the context of a supportive physician-patient relationship.

Vasoactive intestinal polypeptide gene expression is characteristically higher in opossum gastrointestinal sphincters.

BACKGROUND/AIMS: Vasoactive intestinal polypeptide (VIP) has been suggested to be an inhibitory neurotransmitter in the sphincteric and nonsphincteric smooth muscles of the gut. However, the relative gene expression of VIP in these functionally diverse regions is not known. METHODS: The gastrointestinal smooth muscle sphincters of opossums were excised from the adjoining nonsphincteric smooth muscles. RNAs were isolated and subjected to blot hybridizations with VIP complementary DNA probe. Relative expression of VIP gene was quantitated using the densitometric scanning of the VIP messenger RNA (mRNA) transcripts. The cellular specificity of VIP gene expression was investigated in cultures of neuroblastoma cells and myenteric plexuses and compared with those of the smooth muscle cells. RESULTS: The data showed higher levels of VIP mRNA in the sphincteric than the adjoining nonsphincteric tissues. VIP mRNA were found in significantly higher amounts in the myenteric neurons and neuroblastoma cells than in the smooth muscle cells. CONCLUSIONS: VIP gene expression was significantly higher in the sphincteric smooth muscle regions than in the nonsphincteric regions of the gut. The studies provide further evidence for the role of VIP in neurotransmission of the gut.

Pseudorabies virus infection of the rat central nervous system: ultrastructural characterization of viral replication, transport, and pathogenesis.

Pseudorabies virus (PRV) has been used extensively to map synaptic circuits in the CNS and PNS. A fundamental assumption of these studies is that the virus replicates within synaptically linked populations of neurons and does not spread through the extracellular space or by cell-to-cell fusion. In the present analysis we have used electron microscopy to characterize pathways of viral replication and egress that lead to transneuronal infection of neurons, and to document the non-neuronal response to neuronal infection. Three strains of PRV that differ in virulence were used to infect preganglionic motor neurons in the dorsal motor nucleus of the vagus (DMV). The data demonstrate that viral replication and transneuronal passage occur in a stepwise fashion that utilizes existing cellular processes, and that the non-neuronal response to infection serves to restrict nonspecific spread of virus by isolating severely infected neurons. Specifically, capsids containing viral DNA replicate in the cell nucleus, traverse the endoplasmic reticulum to gain access to the cytoplasm, and acquire a bilaminar membrane envelope from the trans cisternae of the Golgi. The outer leaf of this envelope fuses with the neuron membrane to release virus adjacent to axon terminals that synapse upon the infected cell. A second fusion event involving the viral envelope and the afferent terminal releases the naked capsid into the bouton. Systematic analysis of serial sections demonstrated that release of virus from infected neurons occurs preferentially at sites of afferent contact. Nonspecific diffusion of virus from even the most severely infected cells is restricted by astrocytes and other non-neuronal elements that are mobilized to the site of viral infectivity. The ability of glia and macrophages to restrict spread of virus from necrotic neurons is the product of (1) temporal differences in the mobilization of these cells to the site of infection, (2) differential susceptibility of these cells to PRV infection, and (3) abortive viral replication in cells that are permissive for infection. The findings provide further insight into the intracellular routes of viral assembly and egress and support the contention that transneuronal spread of virus in the brain results from specific passage of virions through synaptically linked neurons rather than through cell fusion or release of virus into the extracellular space.

The central organization of the vagus nerve innervating the colon of the rat.

BACKGROUND: The extent to which the vagus nerve innervates the colon remains controversial. METHODS: In 29 rats the tracer cholera toxin-horseradish peroxidase was injected into the cecum, the ascending, transverse, or descending colon or the rectum. For comparison, control injections were made into the stomach. RESULTS: For all areas of colon except the rectum, brainstem motoneuronal labeling was limited to the lateral third of the dorsal motor nucleus of the vagus nerve bilaterally. In contrast, gastric injections resulted in motoneuronal labeling limited to the medial portions of the nucleus. The number of labeled motoneurons was greatest following injection of the cecum, and it significantly decreased for the more distal areas of the colon. Colonic motoneuron dendrites projected into the nucleus of the solitary tract and within the dorsal motor nucleus of the vagus nerve. Sensory afferent terminal labeling was limited to the commissural and medial subnuclei of the nucleus of the solitary tract. For the rectum, sensory and motor labeling was limited to the spinal cord. CONCLUSIONS: The distribution of labeling within the vagal complex indicates that all regions of the colon, except the rectum, are innervated by the celiac and accessory celiac branches of the vagus nerve.

Calcitonin gene-related peptide in nucleus ambiguus motoneurons in rat: viscerotopic organization.

Calcitonin gene-related peptide has been reported in the rat nucleus ambiguus. This nucleus comprises a dorsal division that is the source of special visceral efferents innervating the striated muscle of the upper alimentary tract and a ventral division supplying general visceral efferents primarily to the heart. The distribution of calcitonin gene-related peptide immunoreactive neurons in the two divisions was determined by using a combination of immunocytochemical techniques and fluorescent retrograde tracing. In 22 rats, injections of Fluoro-Gold were made into either the supranodosal vagus nerve, palatopharynx, larynx, esophagus, or heart. Following colchicine injection, medullary sections were processed immunocytochemically for calcitonin gene-related peptide. Injection of Fluoro-Gold into the supranodosal vagus resulted in prominent labeling of neurons in the dorsal and ventral divisions of the nucleus ambiguus. The majority of fluorescent labeled neurons in the dorsal division were found to be immunoreactive for calcitonin gene-related peptide, while those labeled neurons in the ventral division were unreactive for the peptide. With esophageal, and palatopharyngeal and cricothyroid injections, many fluorescent labeled neurons that were immunoreactive for calcitonin gene-related peptide were found respectively in the compact and semicompact formations of the dorsal division. In contrast, injections of the heart resulted in fluorescent labeled neurons, which were unreactive for calcitonin gene-related peptide, localized to the external formation. The results demonstrate that calcitonin gene-related peptide immunoreactive neurons are localized entirely to the dorsal division of the nucleus ambiguus and that all striated muscular areas of the alimentary tract are innervated by calcitonin gene-related peptide containing motoneurons. The localization of calcitonin gene-related peptide to vagal motoneurons also known to contain acetylcholine and the increase in acetylcholine receptor synthesis caused by this peptide suggest that calcitonin gene-related peptide acts as a cotransmitter with acetylcholine in special visceral efferent vagal motoneurons.

Mechanisms of esophageal pain.

Esophageal pain is transmitted via the sympathetic nervous system to the spinal cord, in which pain from visceral and somatic sources ascends to higher centers in the brain. Primary afferent neurons are bipolar, with the peripheral end specialized to be a sensory receptor. Nociceptors of somatosensory afferents are free nerve endings that can be activated by mechanical, thermal, or chemical stimuli. Esophageal nociceptive neurons have not been specifically identified but probably are also free nerve endings. Most esophageal spinal mechanoreceptors have been shown to be nociceptive. Some esophageal mechanonociceptors have a wide dynamic range and respond to physiologic and painful stimuli, while others have a high threshold of stimulation and are solely nociceptive. Esophageal spinal afferents have their cell bodies in the dorsal root ganglia and contain substance P and calcitonin gene-related peptide. These putative neurotransmitters are transported in both the peripheral and central directions of bipolar afferent neurons. Primary afferent neurons are likely to also contain an excitatory amino acid neurotransmitter such as glutamate. Centrally, nociceptive primary afferents terminate on neurons in specific layers of the dorsal horn of the spinal cord. Convergence of multiple visceral afferents with somatic afferents onto the same dorsal horn neurons may explain referred pain. A patient's inability to distinguish esophageal from cardiac pain may be due to convergence of pain pathways. Second-order neurons in the dorsal horn project in the anterolateral system to the brain. Within the anterolateral system, nociception ascends in the spinothalamic, spinoreticular, and spinomesencephalic tracts. The thalamus relays fast pain to the postcentral areas of the parietal lobe of the cortex. Pathways to the reticular formation are slow and may mediate the increased arousal that occurs in response to pain. The spinomesencephalic tract projects to midbrain sites including the periaqueductal gray. Organ-specific pathways in the brain have yet to be defined, but neuroanatomic tracing techniques employing neurotropic viruses are being developed. The perception of pain can be influenced at multiple levels, such as the receptor in the esophagus, the synapses in the dorsal horn of the spinal cord or thalamus, or the cortex. A fundamental mechanism of modulating nociception is descending inhibition.(ABSTRACT TRUNCATED AT 400 WORDS)