Visceral Nociception Research Articles

A nociceptive stress model of adolescent physical abuse induces contextual fear and cingulate nociceptive neuroplasticities.

Adolescent physical abuse impairs emotional development and evokes cingulate pathologies, but its neuronal and circuit substrates are unknown. Conditioning adolescent rabbits with noxious colorectal distension for only 2h over 3weeks simulated the human child abuse in amplitude, frequency, and duration. Thermal withdrawal thresholds were unchanged suggesting that sensitized spinal mechanisms may not be operable. Unchanged weight, stools, colorectal histology, and no evidence of abdominal pain argue against tissue injury or irritable bowel syndrome. Contextual fear was amplified as they avoided the site of their abuse. Conditioning impacted anterior cingulate and anterior midcingulate (ACC, aMCC) neuron excitability: (1) more neurons responded to cutaneous and visceral (VNox) noxious stimuli than controls engaging latent nociception (present but not manifest in controls). (2) Rear paw stimulation increased responses over forepaws with shorter onsets and longer durations, while forepaw responses were of higher amplitude. (3) There were more VNox responses with two excitatory phases and longer durations. (4) Some had unique three-phase excitatory responses. (5) Long-duration VNox stimuli did not inhibit neurons as in controls, suggesting the release of an inhibitory circuit. (6) aMCC changes in cutaneous but not visceral nociception confirmed its role in cutaneous nociception. For the first time, we report neuroplasticities that may be evoked by adolescent physical abuse and reflect psychogenic pain: i.e., no ongoing peripheral pain and altered ACC nociception. These limbic responses may be a cognitive trace of abuse and may shed light on impaired human emotional development and sexual function.

The 5-HT4 receptor-mediated inhibition of visceral nociceptive neurons in the rat caudal ventrolateral medulla

Activation of the serotonin type 4 (5-HT4) receptors has been reported to improve abdominal pain in patients with functional gastrointestinal disorders and reduce visceral nociception in animal models. Earlier studies have proposed that 5-HT4 agonist can produce visceral analgesia by acting at the supraspinal level, but the underlying neuronal mechanisms remain unclear. The caudal ventrolateral medulla (CVLM) is the first site for processing of visceral nociceptive signals ascending via spinal pathways and an important component of the endogenous pain modulatory system. Therefore, the objective of the present study was to examine whether activation of 5-HT4 receptors can affect the visceral pain-related neurons in the CVLM. In urethane-anesthetized adult male Wistar rats, we evaluated the effects of a 5-HT4 receptor agonist, BIMU8 on ongoing firing of the CVLM neurons and their excitatory responses to noxious colorectal distension (CRD, 80mmHg). The drug’s effect was also tested on blood pressure reactions induced by CRD–a general physiological measure of visceral nociception. Intravenous administration of BIMU8 (0.5, 1 or 2mg/kg) produced dose-dependent suppression of both the ongoing and CRD-evoked activities of the CVLM neurons and simultaneously attenuated the depressor hemodynamic reaction to CRD. The compound’s inhibitory effect was almost completely eliminated by intracerebroventricular pretreatment with GR113808, a selective 5-HT4 antagonist, indicating the preferential involvement of supraspinal 5-HT4 receptors. Results indicate that visceral nociceptive transmission through the caudal medulla is negatively modulated by descending 5-HT4-dependent mechanisms. These findings can contribute to a deeper understanding of supraspinal processing of pain signals from the abdomen.

Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity.

Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.

1130 - MrgprC11 Expression and Function in Vagal Afferent Neurons in the Esophagus: A Novel Mechanism Underlying Visceral Sensation and Nociception

1130 - MrgprC11 Expression and Function in Vagal Afferent Neurons in the Esophagus: A Novel Mechanism Underlying Visceral Sensation and Nociception

MP31-18 SPINAL CORD STIMULATION ATTENUATES VISCERAL PAIN-RELATED VISCEROMOTOR REFLEXES IN RODENTS WITH CYCLOPHOSPHAMIDE-INDUCED CYSTITIS

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Non-neurogenic Voiding Dysfunction I1 Apr 2017MP31-18 SPINAL CORD STIMULATION ATTENUATES VISCERAL PAIN-RELATED VISCEROMOTOR REFLEXES IN RODENTS WITH CYCLOPHOSPHAMIDE-INDUCED CYSTITIS Jih-Chao Yeh, David A Ginsberg, Larissa V Rodriguez, and Huiyi Harriet Chang Jih-Chao YehJih-Chao Yeh More articles by this author , David A GinsbergDavid A Ginsberg More articles by this author , Larissa V RodriguezLarissa V Rodriguez More articles by this author , and Huiyi Harriet ChangHuiyi Harriet Chang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.972AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic inflammation that results in recurring pain in the bladder and the surrounding pelvic region caused by abnormal excitability of micturition reflexes. Spinal cord stimulation (SCS) is currently in clinical use for the attenuation of neuropathic pain, and has been identified for amelioration of pain in a rodent model of colorectal distention. This study aimed to investigate the potential effect of SCS on attenuation of visceral pain-related visceromotor reflexes (VMR) in rodents with cyclophosphamide-induced cystitis. METHODS Female Sprague-Dawley rats underwent intraperitoneal injection of cyclophosphamide (CYP, n=8) or saline (controls, n=4). 48 hours after CYP or saline injections, all rats underwent surgical preparations under urethane anesthesia. Stimulation wires were placed on the dorsal surface of the spinal segments of L2 and L3 for SCS. A PE-50 tubing was inserted into the bladder to obtain the intravesical pressure (IVP). Two wires are placed in the left external abdominal oblique muscle to record VMR. Before and after SCS (40 Hz, 0.2 ms for 25 min), VMR and maximum intravesical pressure (IVPmax) were obtained during continuous bladder infusion and isotonic bladder distention (IBD). RESULTS During continuous bladder infusion (Fig 1A), the ratio of VMR threshold/IVPmax was significantly decreased in CYP rats indicating early VMR appearance compared to controls. SCS significantly increased the ratio indicating the delayed VMR appearance. During IBD with urethral occlusion, SCS delayed the latency of VMR appearance in CYP rats below the voiding thresholds at 10 and 20 cmH2O. SCS also significantly decreased VMR area under the curve (AUC) in CYP rats (Figs 1B-C). CONCLUSIONS SCS attenuated visceral pain-related VMR in rats with CYP-induced cystitis suggesting a role for SCS in modulating visceral nociception and hyperalgesia. SCS appears to be a potential treatment of IC/PBS. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e406 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jih-Chao Yeh More articles by this author David A Ginsberg More articles by this author Larissa V Rodriguez More articles by this author Huiyi Harriet Chang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Peripheral KV7 channels regulate visceral sensory function in mouse and human colon.

BackgroundChronic visceral pain is a defining symptom of many gastrointestinal disorders. The KV7 family (KV7.1–KV7.5) of voltage-gated potassium channels mediates the M current that regulates excitability in peripheral sensory nociceptors and central pain pathways. Here, we use a combination of immunohistochemistry, gut-nerve electrophysiological recordings in both mouse and human tissues, and single-cell qualitative real-time polymerase chain reaction of gut-projecting sensory neurons, to investigate the contribution of peripheral KV7 channels to visceral nociception.ResultsImmunohistochemical staining of mouse colon revealed labelling of KV7 subtypes (KV7.3 and KV7.5) with CGRP around intrinsic enteric neurons of the myenteric plexuses and within extrinsic sensory fibres along mesenteric blood vessels. Treatment with the KV7 opener retigabine almost completely abolished visceral afferent firing evoked by the algogen bradykinin, in agreement with significant co-expression of mRNA transcripts by single-cell qualitative real-time polymerase chain reaction for KCNQ subtypes and the B2 bradykinin receptor in retrogradely labelled extrinsic sensory neurons from the colon. Retigabine also attenuated responses to mechanical stimulation of the bowel following noxious distension (0–80 mmHg) in a concentration-dependent manner, whereas the KV7 blocker XE991 potentiated such responses. In human bowel tissues, KV7.3 and KV7.5 were expressed in neuronal varicosities co-labelled with synaptophysin and CGRP, and retigabine inhibited bradykinin-induced afferent activation in afferent recordings from human colon.ConclusionsWe show that KV7 channels contribute to the sensitivity of visceral sensory neurons to noxious chemical and mechanical stimuli in both mouse and human gut tissues. As such, peripherally restricted KV7 openers may represent a viable therapeutic modality for the treatment of gastrointestinal pathologies.

Emerging studies of human visceral nociceptors.

Animal studies have led to significant advances in our understanding of pain mechanisms in the intestine that could lead to altered signaling in disorders such as irritable bowel syndrome. However, how these translate to the human afferent nervous system is unclear. Recent studies have demonstrated that it is possible to use a variety of techniques, including electrophysiological recordings, to begin to examine these concepts in humans. This mini-review examines these studies to explore how well animal studies translate to humans suffering from irritable bowel syndrome, highlights some of the advantages and technical limitations of these approaches, and identifies some priorities for future studies using human tissues.

TRPA1 in the spinal dorsal horn is involved in post-inflammatory visceral hypersensitivity: in vivo study using TNBS-treated rat model.

IntroductionThe transient receptor potential ankyrin-1 (TRPA1) channel, a pain transducer and amplifier, is drawing increasing attention in the field of visceral hypersensitivity, commonly seen in irritable bowel syndrome and inflammatory bowel disease. However, the role of TRPA1 in visceral nociception during post-inflammatory states is not well defined. Here, we explore the correlation between TRPA1 expression in the spinal dorsal horn (SDH) and persistent post-inflammatory visceral hypersensitivity.MethodsWe injected rats intracolonically with 2,4,6-trinitrobenzene sulfonic acid (TNBS) or vehicle (n=12 per group). Post-inflammatory visceral hypersensitivity was assessed by recording the electromyographic activity of the external oblique muscle in response to colorectal distension. TRPA1 expression and distribution in the spinal cord and colon were examined by Western blotting and immunohistochemistry.ResultsAnimals exposed to TNBS had more abdominal contractions than vehicle-injected controls (P<0.05), which corresponded to a lower nociceptive threshold. Expression of TRPA1 in the SDH (especially in the substantia gelatinosa) and the colon was significantly greater in the TNBS-treated group than in controls (P<0.05). In the SDH, the number of TRPA1-immunopositive neurons was 25.75±5.12 in the control group and 34.25±7.89 in the TNBS-treated group (P=0.023), and integrated optical density values of TRPA1 in the control and TNBS-treated groups were 14,544.63±6,525.54 and 22,532.75±7,608.11, respectively (P=0.041).ConclusionOur results indicate that upregulation of TRPA1 expression in the SDH is associated with persistent post-inflammatory visceral hypersensitivity in the rat and provides insight into potential therapeutic targets for the control of persistent visceral hypersensitivity.

Imaging activation of peptidergic spinal afferent varicosities within visceral organs using novel CGRPα-mCherry reporter mice.

In vertebrates, visceral pain from internal organs is detected by spinal afferents, whose cell bodies lie in dorsal root ganglia (DRG). Until now, all recordings from spinal afferents have been restricted to recording transmission of action potentials along axons, or from cell bodies lying outside their target organ, which is not where sensory transduction occurs. Our aim was to record directly from a major class of spinal afferent within visceral organs, where transduction of sensory stimuli into action potentials occurs. Using novel calcitonin gene-related peptide (CGRP)α reporter mice, DRG neurons expressed mCherry, including nerve axons within viscera. In colon, a minority of total CGRP immunoreactivity was attributed CGRPα. In isolated unstretched colon, calcium imaging from CGRPα-expressing varicose axons did not detect resolvable calcium transients. However, noxious levels of maintained circumferential stretch to the colon induced repetitive calcium transients simultaneously in multiple neighboring varicosities along single mCherry-expressing axons. Discrete varicosities could generate unitary calcium transients independently of neighboring varicosities. However, axons expressing mCherry only generated coordinated calcium transients when accompanied by simultaneous activation of multiple varicosities along that axon. Simultaneous imaging from different classes of myenteric neurons at the same time as mCherry-expressing axons revealed coordinated calcium transients in multiple myenteric neurons, independent of activity in mCherry-expressing axons. CGRPα-expressing axon terminals preferentially responded to heat, capsaicin, and low pH. We show that direct recordings can be made from the major class of peptidergic spinal afferent that contributes to visceral nociception. This approach can provide powerful insights into transduction of stimuli in viscera.

Ex vivo study of human visceral nociceptors

ObjectiveThe development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that...

Physiology of Visceral Pain.

Pain involving thoracic, abdominal, or pelvic organs is a common cause for physician consultations, including one-third of chronic pain patients who report that visceral organs contribute to their suffering. Chronic visceral pain conditions are typically difficult to manage effectively, largely because visceral sensory mechanisms and factors that contribute to the pathogenesis of visceral pain are poorly understood. Mechanistic understanding is particularly problematic in "functional" visceral diseases where there is no apparent pathology and pain typically is the principal complaint. We review here the anatomical organization of the visceral sensory innervation that distinguishes the viscera from innervation of all other tissues in the body. The viscera are innervated by two nerves that share overlapping functions, but also possess notably distinct functions. Additionally, the visceral innervation is sparse relative to the sensory innervation of other tissues. Accordingly, visceral sensations tend to be diffuse in character, are typically referred to nonvisceral somatic structures and thus are difficult to localize. Early arguments about whether the viscera were innervated ("sensate") and later, whether innervated by nociceptors, were resolved by advances reviewed here in the anatomical and functional attributes of receptive endings in viscera that contribute to visceral pain (i.e., visceral nociceptors). Importantly, the contribution of plasticity (i.e., sensitization) of peripheral and central visceral nociceptive mechanisms is considered in the context of persistent, chronic visceral pain conditions. The review concludes with an overview of the functional anatomy of visceral pain processing. © 2016 American Physiological Society. Compr Physiol 6:1609-1633, 2016.

Role of transient receptor potential melastatin 2 (TRPM2) channels in visceral nociception and hypersensitivity

Transient receptor potential melastatin 2 (TRPM2) is a thermosensitive, Ca2+-permeable cation channel. TRPM2 contributes to the pathogenesis of inflammatory bowel disease, and inflammatory and neuropathic pain. We hypothesized that TRPM2 is important for visceral nociception and the development of visceral hypersensitivity. Therefore, we investigated the expression of TRPM2 channels and their involvement in visceral nociception in normal physiology and under pathological conditions that cause visceral hypersensitivity in rats. TRPM2 immunoreactivities were detected in the mucosa and muscle layer of the rat gastrointestinal tract. TRPM2 immunopositive cell bodies were almost completely co-localized with calretinin- and NeuN-positive cells in the myenteric plexus. We found that the majority of the TRPM2-immunoreactive cells were double-labeled with the retrograde marker fluorogold in lumbar 6/sacral 1 dorsal root ganglia (DRG), indicating that TRPM2 is expressed in spinal primary afferents innervating the distal colon. Subtypes of TRPM2-immunopositive DRG neurons were labeled by the A-fiber marker NF200, the C-fiber marker IB4, substance P, calcitonin gene-related peptide, or P2X3 receptor. We found that oral administration of the TRPM2 inhibitor econazole (30mg/kg) reduced the visceromotor response (VMR) to noxious colorectal distention (CRD) at 80mmHg in control rats. Expression of TRPM2 in the mucosa of the distal colon was increased in a trinitrobenzene sulfonic acid-induced colitis model. The VMR to CRD significantly increased in colitis model rats compared with control rats at 40, 60, and 80mmHg. Econazole restored visceral hypersensitivity to the control level. Furthermore, TRPM2-deficient mice showed significantly attenuated trinitrobenzene sulfonic acid induced visceral hypersensitivity compared with wild-type mice. In conclusion, TRPM2 channels contribute to visceral nociception in response to noxious stimuli under normal conditions and visceral hypersensitivity in pathological conditions.

Sex differences in stress-induced visceral hypersensitivity following early life adversity: a two hit model.

Early life adversity (ELA) has been indicated as a risk factor for the development of stress axis dysfunction in adulthood, specifically in females. We previously showed that unpredictable ELA induces visceral hyperalgesia in adult female rats. It remains to be determined whether ELA alters visceral nociceptive responses to stress in adulthood. The current study tested the hypothesis that following ELA, exposure to an adulthood stressor, or second hit, serves as a risk factor for exaggerated stress-induced visceral hypersensitivity that is sex-specific. Following ELA, adult stress was induced via a single exposure (acute) or repetitive daily exposure, 1 h/day for 7 days (chronic), to water avoidance stress (WAS). Acute WAS increased pain behaviors in all adult female rats, however, females that experienced unpredictable ELA exhibited significantly more pain behaviors compared to those exposed to predictable ELA or controls. Following chronic WAS, all adult females exhibited increased pain responses, however, an exaggerated response was observed in rats exposed to unpredictable or predictable ELA compared to controls. Similarly, in adult male rats exposure to acute or chronic WAS increased pain behaviors, however, there were no differences in pain behaviors between ELA groups. This study highlights a novel consequence of ELA on stress-induced visceral nociception in adulthood that is sex-specific. More importantly, our study suggests that ELA not only serves as a risk factor for development of chronic pain in adulthood, but also serves as a predisposition for worsening of visceral pain following adult stress in female rats.

Obesity Takes Its Toll on Visceral Pain: High-Fat Diet Induces Toll-Like Receptor 4-Dependent Visceral Hypersensitivity.

Exposure to high-fat diet induces both, peripheral and central alterations in TLR4 expression. Moreover, functional TLR4 is required for the development of high-fat diet-induced obesity. Recently, central alterations in TLR4 expression have been associated with the modulation of visceral pain. However, it remains unknown whether there is a functional interaction between the role of TLR4 in diet-induced obesity and in visceral pain. In the present study we investigated the impact of long-term exposure to high-fat diet on visceral pain perception and on the levels of TLR4 and Cd11b (a microglial cell marker) protein expression in the prefrontal cortex (PFC) and hippocampus. Peripheral alterations in TLR4 were assessed following the stimulation of spleenocytes with the TLR4-agonist LPS. Finally, we evaluated the effect of blocking TLR4 on visceral nociception, by administering TAK-242, a selective TLR4-antagonist. Our results demonstrated that exposure to high-fat diet induced visceral hypersensitivity. In parallel, enhanced TLR4 expression and microglia activation were found in brain areas related to visceral pain, the PFC and the hippocampus. Likewise, peripheral TLR4 activity was increased following long-term exposure to high-fat diet, resulting in an increased level of pro-inflammatory cytokines. Finally, TLR4 blockage counteracted the hyperalgesic phenotype present in mice fed on high-fat diet. Our data reveal a role for TLR4 in visceral pain modulation in a model of diet-induced obesity, and point to TLR4 as a potential therapeutic target for the development of drugs to treat visceral hypersensitivity present in pathologies associated to fat diet consumption.

261 Low FODMAP Diet Modulates Visceral Nociception by Changing Gut Microbiota and Intestinal Permeability in IBS

261 Low FODMAP Diet Modulates Visceral Nociception by Changing Gut Microbiota and Intestinal Permeability in IBS

P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors.

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Nav1.9 in mediating murine responses. The application of UTP (P2Y2 and P2Y4 agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y1, P2Y12, and P2Y13 agonist) also increased action potential firing, an effect blocked by the selective P2Y1 receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y1 and P2Y2 transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Nav1.9 transcripts colocalized in 86% of P2Y1-positive and 100% of P2Y2-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(-/-) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease.

Novel nervous system mechanisms in visceral pain.

Visceral hypersensitivity is an important factor underlying abdominal pain in functional gastrointestinal disorders such as irritable bowel syndrome (IBS) and can result from aberrant signaling from the gut to the brain or vice versa. Over the last two decades, research has identified several selective, intertwining pathways that underlie IBS-related visceral nociception, including specific receptors on afferent and efferent nerve fibers such as transient receptor potential channels (TRP) channels, opioid, and cannabinoid receptors. In this issue of Neurogastroenterology and Motility Gil etal. demonstrate that in an animal model with reduced descending inhibitory control, the sympathetic nervous system outflow is enhanced, contributing to visceral and somatic hypersensitivity. They also provide evidence that interfering with the activation of adrenergic receptors on sensory nerves can be an interesting new strategy to treat visceral pain in IBS. This mini-review places these findings in a broader perspective by providing an overview of promising novel mechanisms to alter the nervous control of visceral pain interfering with afferent or efferent neuronal signaling.

α-Conotoxin Vc1.1 inhibits human dorsal root ganglion neuroexcitability and mouse colonic nociception via GABAB receptors

Objectiveα-Conotoxin Vc1.1 is a small disulfide-bonded peptide from the venom of the marine cone snail Conus victoriae. Vc1.1 has antinociceptive actions in animal models of neuropathic pain, but its applicability...

Central control of visceral pain and urinary tract function.

Afferent input from Aδ and C-fibres innervating the urinary bladder are processed differently by the brain, and have different roles in signaling bladder sensation. Aδ fibres that signal bladder filling activate a spino-bulbo-spinal loop, which relays in the midbrain periaqueductal grey (PAG) and pontine micturition centre (PMC). The excitability of this circuitry is regulated by tonic GABAergic inhibitory processes. In humans and socialised animals micturition is normally under volitional control and influenced by a host of psychosocial factors. Higher nervous decision-making in a social context to 'go now' or 'do not go' probably resides in frontal cortical areas, which act as a central control switch for micturition. Exposure to psychosocial stress can have profoundly disruptive influence on the process and lead to maladaptive changes in the bladder. During sleeping the voiding reflex threshold appears to be reset to a higher level to promote urinary continence. Under physiological conditions C-fibre bladder afferents are normally silent but are activated in inflammatory bladder states and by intense distending pressure. Following prolonged stimulation visceral nociceptors sensitise, leading to a lowered threshold and heightened sensitivity. In addition, sensitization may occur within the central pain processing circuitry, which outlasts the original nociceptive insult. Visceral nociception may also be influenced by genetic and environmental influences. A period of chronic stress can produce increased sensitivity to visceral pain that lasts for months. Adverse early life events can produce even longer lasting epigenetic changes, which increase the individual's susceptibility to developing visceral pain states in adulthood.

Adenosine A1 receptors mediate the intracisternal injection of orexin-induced antinociceptive action against colonic distension in conscious rats

We have recently demonstrated that orexin acts centrally through the brain orexin 1 receptors to induce an antinociceptive action against colonic distension in conscious rats. Adenosine signaling is capable of inducing an antinociceptive action against somatic pain; however, the association between changes in the adenosinergic system and visceral pain perception has not been investigated. In the present study, we hypothesized that the adenosinergic system may be involved in visceral nociception, and thus, adenosine signaling may mediate orexin-induced visceral antinociception. Visceral sensation was evaluated based on the colonic distension-induced abdominal withdrawal reflex (AWR) in conscious rats. Subcutaneous (0.04–0.2mg/rat) or intracisternal (0.8–4μg/rat) injection of N(6)-cyclopentyladenosine (CPA), an adenosine A1 receptor (A1R) agonist, increased the threshold volume of colonic distension-induced AWR in a dose-dependent manner, thereby suggesting that CPA acts centrally in the brain to induce an antinociceptive action against colonic distension. Pretreatment with theophylline, an adenosine antagonist, or 1,3-dipropyl-8-cyclopentylxanthine, an A1R antagonist, subcutaneously injected potently blocked the centrally injected CPA- or orexin-A-induced antinociceptive action against colonic distension. These results suggest that adenosinergic signaling via A1Rs in the brain induces visceral antinociception and that adenosinergic signaling is involved in the central orexin-induced antinociceptive action against colonic distension.