Visceral Pain Processing Research Articles

Modulation of Capsaicin-Evoked Visceral Pain and Referred Hyperalgesia by Protease-Activated Receptors 1 and 2

Protease-activated receptors (PARs) 1 and 2 are expressed in capsaicin-sensitive sensory neurons, being anti- and pro-nociceptive, respectively. Given the possible cross talk between PAR-2 and capsaicin receptors, we investigated if PAR-2 activation could facilitate capsaicin-evoked visceral pain and referred hyperalgesia in the mouse and also examined the effect of PAR-1 activation in this model. Intracolonic (i.col.) administration of capsaicin triggered visceral pain-related nociceptive behavior, followed by referred hyperalgesia. The capsaicin-evoked visceral nociception was suppressed by intraperitoneal (i.p.) TFLLR-NH2, a PAR-1-activating peptide, but not FTLLR-NH2, a control peptide, and unaffected by i.col. TFLLR-NH2. SLIGRL-NH2, a PAR-2-activating peptide, but not LRGILS-NH2, a control peptide, administered i.col., facilitated the capsaicin-evoked visceral nociception 6 – 18 h after administration, while i.p. SLIGRL-NH2 had no effect. The capsaicin-evoked referred hyperalgesia was augmented by i.col. SLIGRL-NH2, but not LRGILS-NH2, 6 – 18 h after administration, and unaffected by i.p. SLIGRL-NH2, and i.p. or i.col. TFLLR-NH2. Our data suggest that PAR-1 is antinociceptive in processing of visceral pain, whereas PAR-2 expressed in the colonic luminal surface, upon activation, produces delayed sensitization of capsaicin receptors, resulting in facilitation of visceral pain and referred hyperalgesia.

Central nervous system processing of human visceral pain in health and disease.

To understand the pathophysiology of anomalous pain in functional gastrointestinal disorders, we must increase our understanding of how the central nervous system processes visceral pain. Over the past decade, novel application of functional brain imaging and electrophysiological techniques has given us the opportunity to study these processes in humans, and this review summarizes the current body of knowledge.

The induction of central sensitization in a human model of visceral pain hypersensitivity is prevented by ketamine, an NMDA receptor antagonist

Male SD rats (3/group) were fitted with an intra-coloinc latex distention balloon and tail vein catheter. 30 rain later, rats were either kept undisturbed (control), injected iv ~nth saline, or the selective CRE2 agonist, hUcn II (at 20 p,g/kg, 0.1 ml). 10 min later CRD was performed at 60 mmHg for 10 min. The visceromotor response (VMR) (# of abdominal contraction/10 min) was monitored. Immediately after the end of the 10 min CRD, rats were perfused with paraformaldehyde/picric acid and spinal cords were immunohistochemically processed for pfiosphoryiated ERK (pERK) alone, or with Substance P (SP) or CRF. RESULTS: The VMR response in saline plus distended rats was significantly higher than control rats ~423s vs 2.3 s 0.8/10 rain). CRD-induced VMR was significantly blunted with prior Ireatment of hUCN II (21.6 • 3.2/10 min). CRD induced pERK, bilaterally, in the primary ~lsceral collateral pathways (lamina I, outer layer of lamina II, around the medial and lateral borders of the dorsal horn, intermediolateral column, lamina V-VII and area X) of L6-S1 spinal cord. There were very few positive cells from non-distended rats. The number of pERK-positive cells per unilateral section of lamina 1-II in saline injected plus distended rats (104 + 29) was greater (p<0.05) than in non-distended rats (1.3 • 0.9). hUcn II pretreatment reduced this response (5.4 • 0.9) and was not different from controls. SPor CRFpositive fibers were adjacent to the pERK-positive neurons. CONCLUSIONS: Painful CRD m rats increases the VMR and activates ERK in the lumbosacral spinal cord. These effects are attenuated by pretreatment with hUcn I[. Phospborylation of ERK may contribute to central processing of CRD-induced visceral pain. hUcn [I may exert its effect through modulation of spinal ERK pathway. Support by NIHDDK57238 (YT) and NIHDDK5723801A1S] (MM).

Differentiation of visceral and cutaneous pain in the human brain.

The widespread convergence of information from visceral, cutaneous, and muscle tissues onto CNS neurons invites the question of how to identify pain as being from the viscera. Despite referral of visceral pain to cutaneous areas, individuals regularly distinguish cutaneous and visceral pain and commonly have contrasting behavioral reactions to each. Our study addresses this dilemma by directly comparing human neural processing of intensity-equated visceral and cutaneous pain. Seven subjects underwent fMRI scanning during visceral and cutaneous pain produced by balloon distention of the distal esophagus and contact heat on the midline chest. Stimulus intensities producing nonpainful and painful sensations, interleaved with rest periods, were presented in each functional run. Analyses compared painful to nonpainful conditions. A similar neural network, including secondary somatosensory and parietal cortices, thalamus, basal ganglia, and cerebellum, was activated by visceral and cutaneous painful stimuli. However, cutaneous pain evoked higher activation bilaterally in the anterior insular cortex. Further, cutaneous but not esophageal pain activated ventrolateral prefrontal cortex, despite higher affective scores for visceral pain. Visceral but not cutaneous pain activated bilateral inferior primary somatosensory cortex, bilateral primary motor cortex, and a more anterior locus within anterior cingulate cortex. Our results reveal a common cortical network subserving cutaneous and visceral pain that could underlie similarities in the pain experience. However, we also observed differential activation patterns within insular, primary somatosensory, motor, and prefrontal cortices that may account for the ability to distinguish visceral and cutaneous pain as well as the differential emotional, autonomic and motor responses associated with these different sensations.

Sex differences of brain serotonin synthesis in patients with irritable bowel syndrome using alpha-[11C]methyl-L-tryptophan, positron emission tomography and statistical parametric mapping.

Irritable bowel syndrome (IBS) is the most common functional bowel disorder and has a strong predominance in women. Recent data suggest that the brain may play an important role in the pathophysiology of IBS in the brain-gut axis. It is strongly suspected that serotonin (5-HT), a neurotransmitter found in the brain and gut, may be related to the pathophysiology of IBS. It is reported that a 5-HT3 antagonist is effective only in female patients with diarrhea-predominant IBS. In the present study, 5-HT synthesis was measured using positron emission tomography, with alpha-[11C]methyl-L-tryptophan as the tracer, in patients with IBS. The aim of the present study was to compare 5-HT synthesis in the IBS patients with that in the controls, and to compare 5-HT synthesis between male and female IBS patients. Six male and six female nonconstipated IBS patients were scanned. Age-matched healthy volunteers were scanned as controls. Eighty minute dynamic scans were performed. Functional 5-HT synthesis images were analyzed using statistical parametric mapping. 5-HT synthesis was greater only in the female IBS patients in the right medial temporal gyrus (multimodal sensory association cortex) compared with the female controls (P<0.001). The greater brain 5-HT synthesis in the female IBS patients than in the controls may be related to the pathological visceral pain processing of the IBS patients, a larger female predominance of the disorder, and the sex difference of the efficacy of the 5-HT3 antagonist in treatment.

Anticipation Plays a Major Role in the Brain Processing of Human Visceral Pain

Anticipation Plays a Major Role in the Brain Processing of Human Visceral Pain

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.

Visceral pain processing in patients with painfull or painless functional bowel disorders

Visceral pain processing in patients with painfull or painless functional bowel disorders

Visceral pain processing in patients with painfull or painless functional bowel disorders

Visceral pain processing in patients with painfull or painless functional bowel disorders

Gastric distention correlates with activation of multiple cortical and subcortical regions

Background & Aims: The pathophysiology of functional dyspepsia may involve abnormal processing of visceral stimuli at the level of the central nervous system. There is accumulating evidence that visceral and somatic pain processing in the brain share common neuronal substrates. However, the cerebral loci that process sensory information from the stomach are unknown. The aim of this study was to localize the human brain regions that are activated by gastric distention. Methods: Brain 15O-water positron emission tomography was performed in 15 right-handed healthy volunteers during baseline and distal gastric distentions to 10 mm Hg, 20 mm Hg, threshold pain, and moderate pain. Pain, nausea, and bloating were rated during baseline and distentions (0–5 scale). Statistical subtraction analysis of brain images was performed between distentions and baseline. Results: Symptoms increased with distending stimulus intensity (maximum pain, 2.1 ± 0.4; nausea, 2.2 ± 0.4; bloating, 3.7 ± 0.2). Paralleling increases in distention stimulus and symptoms, progressive increases in activation (P ≤ 0.05), were observed in the thalami, insula bilaterally, anterior cingulate cortex, caudate nuclei, brain stem periaqueductal gray matter, cerebellum, and occipital cortex. Conclusions: Symptomatic gastric distention activates structures implicated in somatic pain processing, supporting the notion of a common cerebral pain network.GASTROENTEROLOGY 2001;120:369-376

Regional cerebral activation in irritable bowel syndrome and control subjects with painful and nonpainful rectal distention

Background & Aims: Irritable bowel syndrome (IBS) is characterized by visceral hypersensitivity, possibly related to abnormal brain-gut communication. Positron emission tomography imaging has suggested specific central nervous system (CNS) abnormalities in visceral pain processing in IBS. This study aimed to determine (1) if functional magnetic resonance imaging (fMRI) detects CNS activity during painful and nonpainful visceral stimulation; and (2) if CNS pain centers in IBS respond abnormally. Methods: fMRI was performed during nonpainful and painful rectal distention in 18 patients with IBS and 16 controls. Results: Rectal stimulation increased the activity of anterior cingulate (33/34), prefrontal (32/34), insular cortices (33/34), and thalamus (32/34) in most subjects. In IBS subjects, but not controls, pain led to greater activation of the anterior cingulate cortex (ACC) than did nonpainful stimuli. IBS patients had a greater number of pixels activated in the ACC and reported greater intensity of pain at 55–mm Hg distention than controls. Conclusions: IBS patients activate the ACC, a critical CNS pain center, to a greater extent than controls in response to a painful rectal stimulus. Contrary to previous reports, these data suggest heightened pain sensitivity of the brain-gut axis in IBS, with a normal pattern of activation. GASTROENTEROLOGY 2000;118:842-848

A role for the dorsal column in nociceptive visceral input into the thalamus of primates.

A possible role of the dorsal column (DC) in the processing of visceral pain has gained attention after studies in the rat have revealed that the DC transmits a major part of the pelvic visceral nociceptive input from the colon into the thalamus. Furthermore, clinical interventions aimed at interrupting ascending DC axons near the midline were successful in relieving the pain suffered by patients with cancer of the pelvic organs. The purpose of this study was to check whether a DC lesion in monkeys would reduce the responses of thalamic neurons to graded colorectal distension (CRD) as in rats. Experiments were done on anesthetized male monkeys (Macaca fascicularis). Extracellular single cell recordings were made in the ventrolateral complex of the thalamus, mainly the ventral posterolateral (VPL) nucleus, in response to visceral and cutaneous stimulation. Of 80 VPL cells isolated, CRD activated 25, inhibited 25, and had no effect on 30 neurons. The responses of six viscerosensitive VPL neurons were recorded before and after a lesion of the DC at or above the T10 spinal segment. Lesions of other spinal tracts were made after the DC lesion. The results show that the DC lesion significantly reduced the responses of the thalamic neurons tested with CRD by >50%. Lesions of other tracts did not have a consistent effect. These results corroborate findings in the rat and support the proposal that the DC plays an important role in transmitting nociceptive visceral input into the thalamus and subsequently in visceral pain.

Nucleus gracilis: an integrator for visceral and somatic information.

The nucleus gracilis (NG) receives an abundance of visceral input from various abdominal organs and is proposed to play an important role in visceral pain processing. The purpose of this study was to investigate the necessity of the NG for colorectal input into the ventral posterolateral (VPL) nucleus of the thalamus. Single-cell recordings were made from nine VPL cells isolated in nine different male Sprague Dawley rats anesthetized with pentobarbital sodium. Responses of the VPL cells to colorectal distension (CRD) and to cutaneous stimuli were obtained before and after lesioning of the NG. Electrolytic (n = 5) and chemical (n = 4) lesions of the NG were made in different preparations. The chemical lesions were made by injecting a solution of kainic acid into the NG. Kainic acid presumably kills neuronal cell bodies and spares axons of passage. The results indicate that a lesion of the NG, regardless of its type, reduces dramatically the responses of VPL neurons to innocuous cutaneous stimuli, and, to a lesser extent, the responses to CRD. Attenuation of VPL neuronal responses to CRD as well as to innocuous cutaneous stimuli by the NG lesions emphasizes the role of the dorsal column in visceral nociception and suggests that the NG is an integration center for visceral and cutaneous information flowing into the VPL nucleus.

Noxious colorectal distention induced-c-Fos protein in limbic brain structures in the rat

Colorectal distention is a non-invasive stimulus used to study visceral pain processing in the nervous system. In this study, immunocytochemical labeling for the immediate-early gene, c-Fos, was used to map limbic brain structures involved in processing visceral pain. Rats received noxious colorectal distention while loosely restrained or loose restraint without distention (control). The brains were immunostained and the density of Fos-labeled nuclei within areas of the brain associated with limbic function were examined. Many cortical (cingulate; retrosplenial; insular; perirhinal; entorhinal) and subcortical (periaqueductal gray; locus coeruleus; lateral parabrachial area; paraventricular, anterodorsal and centromedian thalamic nuclei; lateral septal area; dorsomedial hypothalamus; cortical amygdala; subiculum) areas were labeled in the control rats, but significantly more Fos was observed in these areas following noxious colorectal distention (CRD). Additional areas were labeled following CRD but not restraint (e.g. infralimbic and prelimbic cortices; mediodorsal thalamic nucleus; central amygdaloid nucleus). The results show that noxious visceral stimuli result in Fos expression in limbic structures that exceeds that induced by restraint stress, suggesting that different pathways and circuits are recruited by stimuli which can produce similar emotional responses.

Noxious colorectal distention induced-c-Fos protein in limbic brain structures in the rat

Colorectal distention is a non-invasive stimulus used to study visceral pain processing in the nervous system. In this study, immunocytochemical labeling for the immediate-early gene, c-Fos, was used to map limbic brain structures involved in processing visceral pain. Rats received noxious colorectal distention while loosely restrained or loose restraint without distention (control). The brains were immunostained and the density of Fos-labeled nuclei within areas of the brain associated with limbic function were examined. Many cortical (cingulate; retrosplenial; insular; perirhinal; entorhinal) and subcortical (periaqueductal gray; locus coeruleus; lateral parabrachial area; paraventricular, anterodorsal and centromedian thalamic nuclei; lateral septal area; dorsomedial hypothalamus; cortical amygdala; subiculum) areas were labeled in the control rats, but significantly more Fos was observed in these areas following noxious colorectal distention (CRD). Additional areas were labeled following CRD but not restraint (e.g. infralimbic and prelimbic cortices; mediodorsal thalamic nucleus; central amygdaloid nucleus). The results show that noxious visceral stimuli result in Fos expression in limbic structures that exceeds that induced by restraint stress, suggesting that different pathways and circuits are recruited by stimuli which can produce similar emotional responses.