Processing Of Visceral Sensation Research Articles

Interoceptive receptive fields and functional architecture of physiological control in the mouse brainstem

Our external senses of sight, smell, sound, touch, and taste enable us to perceive the external world. In addition, our viscerosensory system monitors the physiological state of peripheral organs. This bodily sensory system orchestrates multi-organ physiological responses, regulating feeding, drinking, sickness behaviors, and generating the internal senses such as satiety, hunger, nausea, visceral malaise. In comparison to external sensory systems, the principles that define visceral sensory processing remain poorly defined. We developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus of the solitary tract (NTS), a sensory gateway in the brainstem that receives bodily signals mostly via the vagus nerve. Combining the imaging platform with stimulation of multiple visceral organs, we uncover diverse neuronal responses to internal stimuli, while functionally defined cell-types are highly organized within the NTS. Combining functional imaging with pharmacogenetic manipulations and viral tracing from genetically defined vagal sensory cell types, we show that the highly organized representations of internal senses are generated by vagal axon sorting and higher-order sensory processing within the NTS. Using a newly developed spatially patterned optogenetic stimulation system, we showed that stimulating different spatial domains of the NTS differentially modulates autonomic functions. Together, our study reveals basic coding principles used by the brain to process visceral inputs and sheds light on the treatment of viscerosensory and autonomic diseases, including obesity, diabetes, eating disorders, and neuroimmune diseases. The work was supported by NIH grants to S.D.L. (DP1 AT009497, R01 DK122976 and R01 DK103703), the Food Allergy Science Initiative, and a Leonard and Isabelle Goldenson Postdoctoral Fellowship, a Harvard Brain Science Initiative Young Investigator Transitions Award, and an American Diabetes Association Postdoctoral Fellowship to C.R. S.D.L. is an investigator of the Howard Hughes Medical Institute. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Altered structural covariance and functional connectivity of the insula in patients with Crohn's disease.

Crohn's disease (CD) is a clinically chronic inflammatory bowel disease, which has been shown to be closely related to the brain-gut axis dysfunction. Although traditionally considered to be a limbic region, the insula has also been commonly identified as an abnormal brain region in previous CD-related studies. Structural magnetic resonance imaging (MRI) and resting-state functional MRI images were acquired from 45 CD patients in remission and 40 healthy controls (HCs). Three neuroimaging analysis methods including voxel-based morphometry (VBM), structural covariance, and functional connectivity (FC) were applied to investigate structural and functional alterations of the insulae between the CD patients and HCs. Pearson correlation was then used to examine the relationships between neuroimaging findings and clinical symptoms. Compared with the HCs, CD patients exhibited decreased gray matter volume (GMV) in the left dorsal anterior insula (dAI) and bilateral posterior insula (PI). Taking these three areas including the left dAI, right PI, and left PI as regions of interest (ROIs), differences were observed in the structural covariance and FC of the ROI with several regions between the two groups. After controlling for psychological factors, the differences of several regions involved in emotional processing in GMV in the left dAI, the FC of the dAI, and the right PI were not significant. The FC of the parahippocampus/hippocampus with dAI and PI were negatively correlated with the CD activity index (CDAI). We suggest that the insula-centered structural and/or functional changes may be associated with abnormal visceral sensory processing and related emotional responses in CD patients.

Interoceptive awareness in focal brain-damaged patients.

Interoception is the basic process enabling evaluation of one's own internal state of body, but its alteration in brain-damaged patients has not been adequately investigated. Our study aimed to investigate awareness of visceral and somatosensorial sensations in brain-damaged patients with unilateral stroke. Sixty patients (22 with left brain damage, LP; 25 with right brain damage without neglect, RPN-; and 13 with right brain-damage and extrapersonal and/or personal neglect, RPN+) and 45 healthy controls (HC) completed the Self-Awareness Questionnaire (SAQ), a self-report tool for assessing interoceptive awareness with two domains related to visceral (VD) and somatosensory feelings (SD), respectively. Comparing the SAQ subdomains scores between three groups of patients (LP, RPN-, and RPN+) and HC, we found that RPN+ had significantly lower scores on VD than HC and LP, whereas no significant difference was found on scores of SD between groups. Our results support the hypothesis of a right-hemispheric dominance for "interoceptive neural network" suggesting that processing of visceral sensations would be located mainly in the right hemisphere. Therefore, a careful assessment of interoceptive awareness in clinical practice would be useful to improve rehabilitation and to engage patients with deficit of interoceptive awareness in developing greater accuracy of body signals.

Altered structural and functional connectivity of the insula in functional dyspepsia.

Functional dyspepsia (FD) is a common functional gastrointestinal disease. Neuroimaging studies have identified that insula is involved in the pathogenesis of FD. However, less is known about structural and functional connectivity of insula in FD. In this study, 67 FD patients and 46 healthy controls (HCs) underwent structural MRI, resting-state functional MRI, diffusion tensor imaging (DTI) scans, and clinical assessment. We used the 3 neuroimaging modalities to investigate structural and functional connectivity of insula between FD patients and HCs, and we examined relationships between the neuroimaging findings and clinical symptoms. Compared with HCs, (i) FD patients had decreased gray matter density in right insula according to voxel-based morphometry method, which region was targeted as region of interest for further analysis of structural and functional connectivity; (ii) FD patients had lower connection probability in right anterior insula with right thalamus, right internal capsule (IC), and right external capsule (EC); (iii) FD patients had decreased functional connectivity of the right anterior insula with right thalamus and right pregenual anterior cingulate cortex (pACC); and (iv) FD patients had negative correlation between disease duration and the functional connectivity of right anterior insula with thalamus. The present findings reveal that alterations of structural and/or functional connectivity of right anterior insula with regions, including thalamus, IC, EC, and pACC, may be mainly implicated in abnormalities of visceral sensory processing and related affective responses in FD patients. Finally, this study could enhance understanding of the pathophysiology of FD.

Brain changes in diabetes mellitus patients with gastrointestinal symptoms.

Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies have demonstrated that autonomic nervous system neuropathy and generalized neuropathy of the central nervous system (CNS) may play a major role. This systematic review provides an overview of the neurodegenerative changes that occur as a consequence of diabetes with a focus on the CNS changes and gastrointestinal (GI) dysfunction. Animal models where diabetes was induced experimentally support that the disease induces changes in CNS. Recent investigations with electroencephalography and functional brain imaging in patients with diabetes confirm these structural and functional brain changes. Encephalographic studies demonstrated that altered insular processing of sensory stimuli seems to be a key player in symptom generation. In fact one study indicated that the more GI symptoms the patients experienced, the deeper the insular electrical source was located. The electroencephalography was often used in combination with quantitative sensory testing mainly showing hyposensitivity to stimulation of GI organs. Imaging studies on patients with diabetes and GI symptoms mainly showed microstructural changes, especially in brain areas involved in visceral sensory processing. As the electrophysiological and imaging changes were associated with GI and autonomic symptoms they may represent a future therapeutic target for treating diabetics either pharmacologically or with neuromodulation.

242 Brain Processing of Rectal Sensation in Children With Chronic Functional Constipation

Background and Objective: The pathophysiology underlying pediatric chronic functional constipation (FC) is poorly understood. These children often report loss of sensation of urge to defecate. Functional magnetic resonance imaging (fMRI) studies have been used to unravel brain processing of visceral sensation in adults with functional gastrointestinal disorders. However, brain-imaging data are lacking in both adults and children with constipation. The aim is to investigate the cerebral activity in response to rectal distension in children with FC and in healthy controls (HCs). Methods: 15 patients with FC (8M/7F; mean age 14.3 yrs, range 12-18 yrs) and 15 HCs (6M/9F; mean age 20.1 yrs, range 18-21 yrs) participated. Rectal barostat was performed prior to the fMRI scan. A stepwise pressure-controlled distension protocol was used to determine the pressure threshold for urge sensation. Subjects received 2 sessions of 5 stimulations consisting of repetitions of 30 sec of rectal stimulation with previous defined pressure threshold, followed by 30 sec of rest during acquisition blood oxygenation level-dependent (BOLD) fMRI. Images were acquired on a 3Tesla MRI scanner with an 8-channel SENSE head receive coil. A T2*-weighted echo planar imaging sequence was acquired with: TR/TE=3000/30 ms, slice thickness=3.0 mm, voxel size=1.72 x 1.72 x 3 mm, with 40 axial slices, in ascending mode covering the whole brain. fMRI signal differences were analyzed using SPM8 in Matlab, thresholded at p<0.001. Cerebral activation was defined as BOLD increase during rectal distension and cerebral deactivation as BOLD decrease during rectal distension. Results: FC patients had higher thresholds for urgency than HCs (p<0.001). FC patients needed a mean pressure of 18.2 mmHg above MDP to provoke urge sensation, compared to a mean pressure of 8.6 mmHg above MDP in HCs. The groups were differentiated by both activated and deactivated regions in response to rectal distension. FC patients showed activation in the dorsolateral prefrontal cortex and deactivation in the median somatosensory cortex, insula and amygdala. HCs showed deactivation in the same areas, but in contrast, no regions showed significant activation in response to rectal distension. Conclusion: This is the first study evaluating cerebral processing of rectal sensation in constipated patients. FC patients and HCs had a different pattern of cerebral activation and deactivation during rectal distension, suggesting different neural processing of rectal urge sensation in brain regions previously implicated in adult studies using visceral pain stimuli.

Altered Brain Microstructure Assessed by Diffusion Tensor Imaging in Patients With Diabetes and Gastrointestinal Symptoms

OBJECTIVEIn patients with long-standing diabetes mellitus (DM), there is increasing evidence for abnormal processing of gastrointestinal sensations in the central nervous system. Using magnetic resonance diffusion tensor imaging, we characterized brain microstructure in areas involved in visceral sensory processing and correlated these findings to clinical parameters.RESEARCH DESIGN AND METHODSTwenty-six patients with DM and gastrointestinal symptoms and 23 healthy control subjects were studied in a 3T scanner. The apparent diffusion coefficient (i.e., diffusivity of water) and fractional anisotropy (FA) (i.e., organization of fibers) were assessed in the “sensory matrix” (cingulate cortex, insula, prefrontal and secondary sensory cortex, amygdala, and corona radiata) and in corpus callosum.RESULTSPatients had decreased FA values compared with control subjects in 1) all areas (P = 0.025); 2) anterior (P < 0.001), mid- (P = 0.001), and posterior (P < 0.001) cingulate cortex; 3) prefrontal cortex gray matter (P < 0.001); 4) corona radiata (P < 0.001); 5) secondary sensory cortex (P = 0.008); and 6) anterior white matter (P = 0.045), anterior gray matter (P = 0.002), and posterior gray matter (P = 0.002) insula. No difference was found in corpus callosum (P > 0.05). The microstructural changes in some areas correlated with clinical parameters such as bloating (anterior insula), mental well-being (anterior insula, prefrontal cortex, and mid-cingulated and corona radiata), autonomic function based on electrocardiographic results (posterior insula and anterior cingulate), and presence of gastroparesis (anterior insula).CONCLUSIONSThe findings of this explorative study indicate that microstructural changes of brain areas involved in visceral sensory processing are associated with autonomic dysfunction and therefore may be involved in the pathogenesis of gastrointestinal symptoms in DM patients.

Su1971 The Effects of Oxytocin on Gastric Motility are Mediated by Different Neuronal Pathways in an Iodoacetamide Model of Functional Dyspepsia

Background: Insula represents an important site in the brain for multi-modal convergence and has been implicated in processing of visceral sensation. Earlier fMRI studies in humans (Lawall, et al. Am J Physiol 2008;294:G787-94) have shown activation and sensitization of insula in response to esophageal acid stimulation. However, response characteristics of insular neurons to esophageal chemical and mechanical stimulation have not been studied. Aims: Our aims in this study were: (i) to determine the influence of esophageal acid stimulation on the insular cortex neurons (ICNs) and (ii) to characterize the responses of these neurons to esophageal distension (ED) and colorectal distension (CRD) before and after esophageal acid exposure. Methods: Eleven male rats (SD, 300-400g) were initially anaesthetized with a mixture of α-chloralose (80mg/kg, i.p.) + urethane (800mg/kg, i.p.). The anesthetics were periodically supplemented (i.v.) every 3 hours with one-fourth of the initial dose and the blood pressure was constantly monitored. A craniotomy (Bregma: +2.5 to -2.5 mm, 2.0 to 7.0 mm lateral) was performed to access insular cortex (IC). Extracellular recordings from the ICNs (Bregma: +1.8 to -2.2 mm, 5.0 to 7.4 mm lateral, 5.8 to 7.8 mm dorso-ventral) were made from the neurons that responded to ED (30-60 mmHg) and/or CRD (30-60 mmHg). After characterization of ICNs to visceral stimulation (ED and CRD), 0.1 ml of PBS (0.1M, pH 7.4) was infused slowly (0.1ml/min) into the esophagus followed by the same volume of 0.1N HCl (pH 1.2). The infusate (0.1 ml) was applied three times at 60s, 300s and 540s. The interval of each infusion time was 4 minutes. The ED and CRD were repeated 15 minutes after acid infusion to study the responses of neurons. Results: Fifteen ED or CRD sensitive neurons were studied for their responses to PBS and acid infusion. All neurons (15/15, 100%) exhibited excitation (p<0.05) following acid infusion, whereas PBS had no effect on the responses of these neurons. Eleven EDand 10 CRDresponsive neurons were fully characterized to preand post-acid condition. Following acid infusion, 11/11 (100%) ED-responsive neurons exhibited increased activity in response to ED. In contrast, 10/10 (100%) CRD-responsive neurons exhibited decreased activity during CRD. In addition, acid, but not PBS, infusion increased the spontaneous firing of all recorded neurons and continued for 30 to 45 minutes after cessation of infusion. Conclusions: Intraesophageal acid infusion significantly alters the response characteristics of ICNs in rats. Esophageal acid infusion differentially modulates the activities of ICNs that receive convergent input from esophagus and colon.

Su1970 Effects of Oxytocin on Gastric-Projecting Neurons in a Rat Model of Functional Dyspepsia

Background: Insula represents an important site in the brain for multi-modal convergence and has been implicated in processing of visceral sensation. Earlier fMRI studies in humans (Lawall, et al. Am J Physiol 2008;294:G787-94) have shown activation and sensitization of insula in response to esophageal acid stimulation. However, response characteristics of insular neurons to esophageal chemical and mechanical stimulation have not been studied. Aims: Our aims in this study were: (i) to determine the influence of esophageal acid stimulation on the insular cortex neurons (ICNs) and (ii) to characterize the responses of these neurons to esophageal distension (ED) and colorectal distension (CRD) before and after esophageal acid exposure. Methods: Eleven male rats (SD, 300-400g) were initially anaesthetized with a mixture of α-chloralose (80mg/kg, i.p.) + urethane (800mg/kg, i.p.). The anesthetics were periodically supplemented (i.v.) every 3 hours with one-fourth of the initial dose and the blood pressure was constantly monitored. A craniotomy (Bregma: +2.5 to -2.5 mm, 2.0 to 7.0 mm lateral) was performed to access insular cortex (IC). Extracellular recordings from the ICNs (Bregma: +1.8 to -2.2 mm, 5.0 to 7.4 mm lateral, 5.8 to 7.8 mm dorso-ventral) were made from the neurons that responded to ED (30-60 mmHg) and/or CRD (30-60 mmHg). After characterization of ICNs to visceral stimulation (ED and CRD), 0.1 ml of PBS (0.1M, pH 7.4) was infused slowly (0.1ml/min) into the esophagus followed by the same volume of 0.1N HCl (pH 1.2). The infusate (0.1 ml) was applied three times at 60s, 300s and 540s. The interval of each infusion time was 4 minutes. The ED and CRD were repeated 15 minutes after acid infusion to study the responses of neurons. Results: Fifteen ED or CRD sensitive neurons were studied for their responses to PBS and acid infusion. All neurons (15/15, 100%) exhibited excitation (p<0.05) following acid infusion, whereas PBS had no effect on the responses of these neurons. Eleven EDand 10 CRDresponsive neurons were fully characterized to preand post-acid condition. Following acid infusion, 11/11 (100%) ED-responsive neurons exhibited increased activity in response to ED. In contrast, 10/10 (100%) CRD-responsive neurons exhibited decreased activity during CRD. In addition, acid, but not PBS, infusion increased the spontaneous firing of all recorded neurons and continued for 30 to 45 minutes after cessation of infusion. Conclusions: Intraesophageal acid infusion significantly alters the response characteristics of ICNs in rats. Esophageal acid infusion differentially modulates the activities of ICNs that receive convergent input from esophagus and colon.

Su1972 Characterization of a Rodent Model for Functional MRI Studies of Esophageal Acid Related Sensory Physiology

Background: Insula represents an important site in the brain for multi-modal convergence and has been implicated in processing of visceral sensation. Earlier fMRI studies in humans (Lawall, et al. Am J Physiol 2008;294:G787-94) have shown activation and sensitization of insula in response to esophageal acid stimulation. However, response characteristics of insular neurons to esophageal chemical and mechanical stimulation have not been studied. Aims: Our aims in this study were: (i) to determine the influence of esophageal acid stimulation on the insular cortex neurons (ICNs) and (ii) to characterize the responses of these neurons to esophageal distension (ED) and colorectal distension (CRD) before and after esophageal acid exposure. Methods: Eleven male rats (SD, 300-400g) were initially anaesthetized with a mixture of α-chloralose (80mg/kg, i.p.) + urethane (800mg/kg, i.p.). The anesthetics were periodically supplemented (i.v.) every 3 hours with one-fourth of the initial dose and the blood pressure was constantly monitored. A craniotomy (Bregma: +2.5 to -2.5 mm, 2.0 to 7.0 mm lateral) was performed to access insular cortex (IC). Extracellular recordings from the ICNs (Bregma: +1.8 to -2.2 mm, 5.0 to 7.4 mm lateral, 5.8 to 7.8 mm dorso-ventral) were made from the neurons that responded to ED (30-60 mmHg) and/or CRD (30-60 mmHg). After characterization of ICNs to visceral stimulation (ED and CRD), 0.1 ml of PBS (0.1M, pH 7.4) was infused slowly (0.1ml/min) into the esophagus followed by the same volume of 0.1N HCl (pH 1.2). The infusate (0.1 ml) was applied three times at 60s, 300s and 540s. The interval of each infusion time was 4 minutes. The ED and CRD were repeated 15 minutes after acid infusion to study the responses of neurons. Results: Fifteen ED or CRD sensitive neurons were studied for their responses to PBS and acid infusion. All neurons (15/15, 100%) exhibited excitation (p<0.05) following acid infusion, whereas PBS had no effect on the responses of these neurons. Eleven EDand 10 CRDresponsive neurons were fully characterized to preand post-acid condition. Following acid infusion, 11/11 (100%) ED-responsive neurons exhibited increased activity in response to ED. In contrast, 10/10 (100%) CRD-responsive neurons exhibited decreased activity during CRD. In addition, acid, but not PBS, infusion increased the spontaneous firing of all recorded neurons and continued for 30 to 45 minutes after cessation of infusion. Conclusions: Intraesophageal acid infusion significantly alters the response characteristics of ICNs in rats. Esophageal acid infusion differentially modulates the activities of ICNs that receive convergent input from esophagus and colon.

Why Do Irritable Bowel Syndrome Women Often Have Nausea Symptom?

Why Do Irritable Bowel Syndrome Women Often Have Nausea Symptom?

Gastroparesis: Concepts, Controversies, and Challenges

Patients with gastroparesis often present a challenge to the treating physician. Postprandial symptoms with nausea and vomiting may not only lead to nutritional and metabolic consequences, but also cause significant disruptions to social activities that often center around food. While the definition of gastroparesis focuses on impaired gastric emptying, treatment options that affect gastric function are limited and often disappointing. The female predominance, the mostly idiopathic nature of the illness with a common history of abuse, and coexisting anxiety or depression show parallels with other functional disorders of the gastrointestinal tract. These parallels provided the rationale for some initial studies investigating alternative therapies that target the brain rather than the stomach. This emerging shift in medical therapy comes at a time when clinical studies suggest that gastric electrical stimulation may exert its effects by modulating visceral sensory processing rather than altering gastric motility. Physiologic and detailed anatomic investigations also support a more complex picture with different disease mechanisms, ranging from impaired accommodation to apparent visceral hypersensitivity or decreased interstitial cells of Cajal to inflammatory infiltration of myenteric ganglia. Delayed gastric emptying remains the endophenotype defining gastroparesis. However, our treatment options go beyond prokinetics and may allow us to improve the quality of life of affected individuals.

Beyond neurons: Involvement of urothelial and glial cells in bladder function

The urothelium, or epithelial lining of the lower urinary tract (LUT), is likely to play an important role in bladder function by actively communicating with bladder nerves, smooth muscle, and cells of the immune and inflammatory systems. Recent evidence supports the importance of non-neuronal cells that may extend to both the peripheral and central processes of the neurons that transmit normal and nociceptive signals from the urinary bladder. Using cats diagnosed with a naturally occurring syndrome termed feline interstitial cystitis (FIC), we investigated whether changes in physiologic parameters occur within 3 cell types associated with sensory transduction in the urinary bladder: 1) the urothelium, 2) identified bladder dorsal root ganglion (DRG) neurons and 3) grey matter astrocytes in the lumbosacral (S1) spinal cord. As estrogen fluctuations may modulate the severity of many chronic pelvic pain syndromes, we also examined whether 17beta-estradiol (E2) alters cell signaling in rat urothelial cells. We have identified an increase in nerve growth factor (NGF) and substance P (SP) in urothelium from FIC cats over that seen in urothelium from unaffected (control) bladders. The elevated NGF expression by FIC urothelium is a possible cause for the increased cell body size of DRG neurons from cats with FIC, reported in this study. At the level of the spinal cord, astrocytic GFAP immuno-intensity was significantly elevated and there was evidence for co-expression of the primitive intermediate filament, nestin (both indicative of a reactive state) in regions of the FIC S1 cord (superficial and deep dorsal horn, central canal and laminae V-VIl) that receive input from pelvic afferents. Finally, we find that E2 triggers an estrus-modifiable activation of p38 MAPK in rat urothelial cells. There were cyclic variations with E2-mediated elevation of p38 MAPK at both diestrus and estrus, and inhibition of p38 MAPK in proestrous urothelial cells. Though urothelial cells are often viewed as bystanders in the processing of visceral sensation, these and other findings support the view that these cells function as primary transducers of some physical and chemical stimuli. In addition, the pronounced activation of spinal cord astrocytes in an animal model for bladder pain syndrome (BPS) may play an important role in the pain syndrome and open up new potential approaches for drug intervention.

S1808 Exploring the Neural Processing of Visceral Sensations: the Influence of Sensory, Emotional and Cognitive Factors

S1808 Exploring the Neural Processing of Visceral Sensations: the Influence of Sensory, Emotional and Cognitive Factors

The role of somatosensory cortical regions in the processing of painful gastric fundic distension: an update of brain imaging findings

Painful gastric distension is processed in a network consisting of brainstem, thalamus, insula, anterior cingulate cortex, (lateral) orbitofrontal and prefrontal cortex, superior temporal cortex and cerebellum. However, the role of primary and secondary somatosensory cortical regions (SI/SII) in the processing of visceral sensation or pain in general and gastric sensation in particular remains unclear. The aim of this study was to localize activations in the SI/SII area from our previously published functional brain imaging studies on gastric distension more precisely, using newly available cytoarchitectonic probability maps of SI/SII, implemented in the SPM Anatomy toolbox. In healthy volunteers, we found two clusters to be overlapping with SII (mainly the OP4 subregion) and, to a lesser extent, SI, although this overlap was small in size. In functional dyspepsia patients, we found two clusters to be overlapping with SII (mainly OP4), of which the cluster in the right hemisphere also overlapped with SI. These findings were confirmed in a conjunction analysis of both groups. Activation in right SI/SII was significantly higher in healthy volunteers when formally compared to patients. These results provide more detailed information on the brain processing of gastric sensation, supporting the hypothesis that SI/SII are involved. This is in line with some previously published studies on visceral sensation, but at variance with some other studies. Methodological differences between the brain imaging studies on gastric distension may account for these somewhat discrepant findings.

Neonatal hind paw injury alters processing of visceral and somatic nociceptive stimuli in the adult rat

Abstract Tissue damage during the first few weeks after birth can have profound effects on sensory processing in the adult. We have recently reported that a short-lasting inflammation of the neonatal rat hind paw produces baseline hypoalgesia and exacerbated hyperalgesia after reinflammation of that hind paw in the adult. Because the contralateral hind paw and forepaws also displayed hypoalgesia, we speculated that effects of the initial injury were not somatotopically restricted and would alter visceral sensory processing as well. In the present study we tested this hypothesis by examining the effects of neonatal hind paw injury at P3 or P14 on visceral and somatic sensitivity in the adult rat. In P3 rats, the visceromotor response evoked by colorectal distention in the absence of colonic inflammation was attenuated in carrageenan-treated neonatal rats compared to naïve rats. Colonic inflammation in the adult reversed this hypoalgesia and evoked a level of visceral hyperalgesia similar to naïve rats. There were no consequences of the P14 injury observed in the adult. In a second experiment, colonic inflammation in naïve rats induced viscerosomatic inhibition to thermal stimulation of the forepaw and hind paw. This inhibition was reversed, and the paw withdrawal latency was slightly decreased in neonatal (P3) carrageenan-treated rats. Rats treated on P14 appeared similar to naïve rats. These data support the hypothesis that neonatal hind paw injury during a critical period permanently alters sensory processing of multiple sensory modalities in the adult. Animals develop with greater inhibitory processing of somatic and visceral stimuli throughout the neuraxis. However, inflammation in the adult in previously uninjured tissue reverses the hypoalgesia and evokes development of normal hyperexcitability associated with tissue injury. Perspective Trauma experienced by premature infants can lead to alterations in sensory processing throughout life. This study shows that short-term somatic tissue injury to neonatal rats during a well-defined critical period alters several aspects of viscerosensory processing in the adult, demonstrating that injury to one tissue affects sensory processing throughout the body.

Human urocortin II, a selective agonist for the type 2 corticotropin-releasing factor receptor, decreases feeding and drinking in the rat.

Corticotropin-releasing factor (CRF) has been hypothesized to modulate consummatory behavior through the Type 2 CRF (CRF(2)) receptor. However, behavioral functions subserved by the CRF(2) receptor remain poorly understood. Recently, human urocortin II (hUcn II), a selective CRF(2) receptor agonist, was identified. To study the effects of this neuropeptide on ingestive behavior, we examined the effects of centrally infused hUcn II (i.c.v. 0, 0.01, 0.1, 1.0, 10.0 micro g) on the microstructure of nose-poke responding for food and water in nondeprived, male rats. Malaise-inducing properties of the peptide were monitored using conditioned taste aversion (CTA) testing. To identify potential sites of action, central induction of Fos protein expression was examined. hUcn II dose dependently reduced the quantity and duration of responding for food and water at doses lower (0.01-1.0 micro g) than that forming a CTA (10 micro g). Effects were most evident during hours 4 to 6 of the dark cycle. Meal pattern analysis showed that hUcn II potently (0.1 micro g) increased the satiating value of food. Rats ate and drank smaller and shorter meals without changing meal frequency. Rats also ate more slowly. hUcn II induced Fos in regions involved in visceral sensory processing and autonomic/neuroendocrine regulation and resembling those activated by appetite suppressants. hUcn II is a promising neuropeptide for investigating the role of the CRF(2) receptor in ingestive behavior.

Differential effects of spinal CNQX on two populations of dorsal horn neurons responding to colorectal distension in the rat

The present study examined the effect of a spinally administered excitatory amino acid antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 1, 2.5, 5 μg) on responses of spinal dorsal horn neurons to graded intensities (20, 40, 60, 80 mmHg) of colorectal distention (CRD). Extracellular single unit recordings were made from 28 dorsal horn neurons in the L6–S2 spinal cord. Neurons excited by CRD were subclassified as short latency abrupt (SLA) neurons and short latency sustained (SLS) neurons. The response to graded intensities of CRD was dose-dependently attenuated in 9/17 SLA neurons (53%). The response to CRD was also dose-dependently attenuated in 8/11 SLS neurons (73%). The response to CRD in the remaining eight SLA neurons and three SLS neurons was not attenuated by CNQX. Comparing only neurons that were significantly attenuated by the CNQX, it was found that the magnitude of attenuation of the response to noxious CRD (80 mmHg) produced by 5 μg CNQX was significantly greater in SLA (63±6%) vs. SLS (40±6%) neurons. While CNQX produced a significant attenuation of the response to innocuous CRD (20 mmHg), there was no difference between the SLA and SLS neurons. The effects of CNQX on the response to somatic stimulation (touch, pinch) of the cutaneous receptive field of these 28 neurons were qualitatively examined in all neurons and quantitatively examined in nine neurons (five SLA and four SLS neurons). CNQX generally decreased the response to pinch or touch, even if CNQX did not attenuate the response to CRD. These results suggest that subpopulations of SLA and SLS neurons are differentially modulated by non-NMDA ionotropic excitatory amino acid receptors and that these neuronal subtypes contribute differently to visceral sensory processing. Furthermore, the lack of correlation between the effects of CNQX on visceral and somatic sensory processing in the same neuron underscores potential differences in processing of visceral and somatic pain.

Evidence for two populations of rat spinal dorsal horn neurons excited by urinary bladder distension

Spinal L6-S2 dorsal horn neurons of cervical spinal cord-transected, decerebrate female rats were characterized using urinary bladder distension (UBD) as a visceral stimulus. Constant pressure, phasic, graded (20–80 mm Hg, 20 s) air UBD was delivered via a transurethral catether and extracellular single-unit recordings obtained from all neurons excited by UBD. Responses to graded UBD and noxious/non-noxious cutaneous stimuli were determined in 258 neurons which could be stratified into two groups based on their effect of a counterirritation stimulus: Type I neurons (n=112) were inhibited by noxious pinch presented in a non-segmental field; Type II neurons (n=146) were not similarly inhibited. Both Types of neurons were identified in both superficial and deep recording sites and demonstrated graded responses to graded UBD. All UBD-excited neurons had convergent cutaneous receptive fields (RFs) excited by non-noxious and/or noxious stimuli. As a group, Type I neurons had a period of decreased activity following termination of the distending stimulus whereas Type II neurons typically had a sustained afterdischarge. UBD-evoked activity in Type II neurons was inhibited more than similar activity in Type I neurons by both intravenous morphine and lidocaine. These results support the assertion that at least two different populations of spinal dorsal horn neurons exist which encode for a stimulus of urinary bladder distension. These populations are an analogue to previously characterized, similar neuronal populations excited by colorectal distension and suggest that they are representative of the overall phenomenon of visceral sensory processing, a component of which is nociception.

Co-expression of P2X receptor subunits on rat nodose neurons that bind the isolectin GS-I-B4.

Triple fluorescent histochemistry was used to describe the types of overlap in visceral sensory neurons (nodose ganglion) for the labeling of the isolectin B4 from Griffonia simplicifolia type one (GS-I-B4) and their immunoreactivity (IR) for two of the ATP receptor subunits (P2X1/3 or P2X2/3). The vast majority of nodose neurons expressed GS-I-B4-binding and most of these displayed P2X receptor IR. Most of the P2X-IR was co-expressed on these individual nodose neurons (P2X1/P2X3 or P2X2/P2X3). A very small subpopulation of neurons that were GS-I-B4 negative but P2X positive displayed a very high relative intensity of P2X3-IR. The functional role that these expression patterns play in visceral sensory processing is currently unclear.