Visceral nociception: peripheral and central aspects of visceral nociceptive systems

Discomfort and pain are the sensations most commonly evoked from viscera. Most nociceptive signals that originate from visceral organs reach the central nervous system (c.n.s.) via afferent fibres in sympathetic nerves, whereas parasympathetic nerves contain mainly those visceral afferent fibres concerned with the non-sensory aspects of visceral afferent function. Noxious stimulation of viscera activates a variety of specific and non-specific receptors, the vast majority of which are connected to unmyelinated afferent fibres. Studies on the mechanisms of visceral sensation can thus provide information on the more general functions of unmyelinated afferent fibres. Specific visceral nociceptors have been found in the heart, lungs, testes and biliary system, whereas noxious stimulation of the gastro-intestinal tract appears to be detected mainly by non-specific visceral receptors that use an intensity-encoding mechanism. Visceral nociceptive messages are conveyed to the spinal cord by relatively few visceral afferent fibres which activate many central neurons by extensive functional divergence through polysynaptic pathways. Impulses in visceral afferent fibres excite spinal cord neurons also driven by somatic inputs from the corresponding dermatome (viscero-somatic neurons). Noxious intensities of visceral stimulation are needed to activate viscero-somatic neurons, most of which can also be excited by noxious stimulation of their somatic receptive fields. The visceral input to some viscero-somatic neurons in the spinal cord can be mediated via long supraspinal loops. Pathways of projection of viscero-somatic neurons include the spino-reticular and spino-thalamic tracts. All these findings give experimental support to the 'convergence-projection' theory of referred visceral pain. Visceral pain is the consequence of the diffuse activation of somato-sensory nociceptive systems in a manner that prevents accurate spatial discrimination or localization of the stimuli. Noxious stimulation of visceral receptors triggers general reactions of alertness and arousal and evokes unpleasant and poorly localized sensory experiences. This type of response may be a feature of sensory systems dominated by unmyelinated afferent inputs.     

Toll-like receptors

Toll-like receptors are a family of transmembrane receptors responsible for recognition and initiation of a response to invading microbes by the immune system. As part of the innate immune system, Toll-like receptors recognise pathogen-associated molecular patterns, highly conserved components that are essential to microbial function. Some of ten toll-like receptors identified in humans are able to recognise several pathogen-associated molecular patterns.     

Roundabout 2 regulates migration of sensory neurons by signaling in trans

BACKGROUND: Roundabout (Robo) receptors and their ligand Slit are important regulators of axon guidance and cell migration. The development of Drosophila embryonic sense organs provides a neuronal migration paradigm where the in vivo roles of Slit and Robo can be assayed using genetics. RESULTS: Here we show that Slit-Robo signaling controls migration of Drosophila larval sensory neurons that are part of the Chordotonal (Cho) stretch receptor organs. We used live imaging to show that abdominal Cho organs normally migrate ventrally during development, whereas thoracic Cho organs do not. Robo2 overexpression in cis (in the sensory neurons) or in trans (on neighboring visceral mesoderm) transforms abdominal organs to a thoracic morphology and position by blocking migration, while loss of Slit-Robo signaling produces a reverse transformation in which thoracic organs migrate ectopically. Rescue and tissue-specific knockout experiments indicate that trans signaling by Robo2 contributes to the normal positioning of the thoracic Cho organs. The differential positioning of Cho organs between the thorax and abdomen is known to be regulated by Hox genes, and we show that the essential Hox cofactor Homothorax, represses Robo2 expression in the abdominal visceral mesoderm. CONCLUSIONS: Our results suggest that segment-specific neuronal migration patterns are directed through a novel signaling complex (the "Slit sandwich") in which Robo2 on the thoracic visceral mesoderm binds to Slit and presents it to Robo receptors on Cho neurons. The differential positioning of Cho organs between thorax and abdomen may be determined by Hox gene-mediated repression of robo2.     

P2X<Subscript>3</Subscript> Receptor Involvement in Pain States

The understanding of how pain is processed at each stage in the peripheral and central nervous system is the precondition to develop new therapies for the selective treatment of pain. In the periphery, ATP can be released from various cells as a consequence of tissue injury or visceral distension and may stimulate the local nociceptors. The highly selective distribution of P2X₃ and P2X_2/3 receptors within the nociceptive system has inspired a variety of approaches to elucidate the potential role of ATP as a pain mediator. Depolarization by ATP of neurons in pain–relevant neuronal structures such as trigeminal ganglion, dorsal root ganglion, and spinal cord dorsal horn neurons are well investigated. P2X receptor-mediated afferent activation appears to have been implicated in visceral and neuropathic pain and even in migraine and cancer pain. This article reviews recently published research describing the role that ATP and P2X receptors may play in pain perception, highlighting the importance of the P2X₃ receptor in different states of pain.     

Recognition of Legionella pneumophila nucleic acids by innate immune receptors

Innate immune receptors evolved to sense conserved molecules that are present in microbes or are released during non-physiological conditions. Activation of these receptors is essential for early restriction of microbial infections and generation of adaptive immunity. Among the conserved molecules sensed by innate immune receptors are the nucleic acids, which are abundantly contained in all infectious organisms including virus, bacteria, fungi and parasites. In this review we focus in the innate immune proteins that function to sense nucleic acids from the intracellular bacterial pathogen Legionella pneumophila and the importance of these processes to the outcome of the infection.     

Innate immunity via Toll-like receptors and Nod proteins

Host defense against microbes requires the development of an efficient immune response aimed to eradicate the source of infection. Through the expression of a battery of germ-line encoded receptors, including the Toll-like receptors and Nod proteins, the innate immune system, which is a prerequisite to the adaptive immune response, detects microbial motifs and initiates pro-inflammatory signaling. Current research into innate immune function focuses on the nature of the ligands detected by this system, the cell signaling that occurs downstream of receptor activation and finally, how these signals culminate into a tailored adaptive immune response directed to eradicate a specific infection.     

Microbes' roadmap to neurons

The nervous system is protected by barriers that restrict the invasion of pathogens. Nevertheless, mechanisms have evolved by which microbes can pass these barriers, enter and exit neurons and target various regions of the nervous system. In the brain, immune responses to pathogens are generally not robust, so microbes can hide and survive or, conversely, cause severe uncontrolled infections. Depending on their sites of entry and the regions that they target, microbes can cause diverse nervous system dysfunctions and even influence host behaviour to their own advantage. This Review discusses routes by which microbes can reach the nervous system and cause persistent or life-threatening infections.     

The role of dorsal columns pathway in visceral pain

Traditionally, the dorsal column-medial lemniscus system has been viewed as a pathway not involved in pain perception. However, recent clinical and experimental studies have provided compelling evidence that implicates an important role of the dorsal column pathway in relaying visceral nociceptive information. Several clinical studies have shown that a small lesion that interrupts fibers of the dorsal columns (DC) that ascend close to the midline of the spinal cord significantly relieves pain and decreases analgesic requirements in patients suffering from cancer originating in visceral organs. Behavioral, electrophysiological and immunohistochemical methods used under experimental situations in animals showed that DC lesion lead to decreased activation of thalamic and gracile neurons by visceral stimuli, suppressed inhibition of exploratory activity induced by visceral noxious stimulation and prevented potentiation of visceromotor reflex evoked by colorectal distention under inflammatory conditions. Whereas the surgical lesion of the DC tract has proven to be clinically successful, a pharmacological approach would be a better strategy to block this pathway and thus to improve visceral pain conditions under less dramatic circumstances than cancer pain. Our finding that PSDC neurons start to express receptors for substance P after colon inflammation suggests new targets for the development of pharmacological strategies for the control of visceral pain.     

Host innate immune receptors and beyond: making sense of microbial infections

The complexity of the immune system mirrors its manifold mechanisms of host-microbe interactions. A relatively simplified view was posited after the identification of host innate immune receptors that their distinct mechanisms of sensing "microbial signatures" create unique molecular switches to trigger the immune system. Recently, more sophisticated and cooperative strategies for these receptors have been revealed during receptor-ligand interactions, trafficking, and intra- and intercellular signaling, in order to deal with a diverse range of microbes. Continued mapping of the complex networks of host-microbe interactions may improve our understanding of self/non-self discrimination in immunity and its intervention.     

Nicotinic mechanisms in the autonomic control of organ systems

Most visceral organs are under the control of the autonomic nervous system (ANS). Information on the state and function of these organs is constantly relayed to the central nervous system (CNS) by sensory afferent fibers. The CNS integrates the sensory inputs and sends neural commands back to the organ through the ANS. The autonomic ganglia are the final site for the integration of the message traveling from the CNS. Nicotinic acetylcholine receptors (nAChRs) are the main mediators of fast synaptic transmission in ganglia, and therefore, are key molecules for the processing of neural information in the ANS. This review focuses on the role of nAChRs in the control of organ systems such as heart, gut, and bladder. The autonomic control of these organ systems is discussed in the light of the results obtained from the analysis of mice carrying mutations targeted to nAChR subunits expressed in the ANS.     

Visceral pain: gut microbiota,a new hope?

Background

Visceral pain is a complex and heterogeneous disorder, which can range from the mild discomfort of indigestion to the agonizing pain of renal colic. Regulation of visceral pain involves the spinal cord as well as higher order brain structures. Recent findings have linked the microbiota to gastrointestinal disorders characterized by abdominal pain suggesting the ability of microbes to modulate visceral hypersensitivity and nociception to pain.

Main body

In this review we describe the neuroanatomical basis of visceral pain signaling and the existing evidence of its manipulation exerted by the gut microbiota. We included an updated overview of the potential therapeutic effects of dietary intervention, specifically probiotics and prebiotics, in alleviating hypersensitivity to visceral pain stimuli.

Conclusions

The gut microbiota dramatically impacts normal visceral pain sensation and affects the mechanisms mediating visceral nociception. Furthermore, manipulation of the gut microbiota using prebiotics and probiotics plays a potential role in the regulation of visceral pain disorders.

     

Periviscerokinin-like immunoreactivity in the nervous system of the American cockroach

A highly specific polyclonal antiserum has been raised against periviscerokinin, the first neuropeptide isolated from the perisympathetic organs of insects (Predel et al. 1995). In this study, two different neuronal systems with periviscerokinin-like immunoreactivity were distinguished in the central nervous system of the American cockroach: (1) An intrinsic neuronal network, restricted to the head-thoracic region, was formed by intersegmental projecting neurons of the brain, suboesophageal ganglion and metathoracic ganglion. In addition, groups of local interneurons occurred in the proto- and tritocerebrum. (2) A typical neurohormonal system was stained exclusively in the abdomen; it was represented by abdominal perisympathetic organs which were supplied by three cell clusters located in each unfused abdominal ganglion. As revealed by nickel backfills, most neurons with axons entering the perisympathetic organs contained a periviscerokinin-like peptide. Immunoreactive fibres left the perisympathetic organs peripherally, innervated the hyperneural muscle and ran via the link nerves/segmental nerves to the heart and segmental vessels. All visceral muscles innervated by periviscerokinin-immunoreactive fibres were shown to be sensitive to periviscerokinin, whereas the hindgut gave no specific response to this peptide.     

Role of nonsynaptic communication in regulating the immune response

The discovery of nonsynaptic communication in the 1960s and 1970s was an important milestone in investigating the function of the nervous system, and it revolutionized our view about information transmission between neurons. In addition, nonsynaptic communication has a practical importance not only within the nervous system, but in the communication between the peripheral nervous system and other organ systems. Nonsynaptic communication takes place in different immune organs, which are innervated by sympathetic nerve terminals. In addition, the function of microglia, one of the immunocompetent cell types of the brain, can also be affected by neurotransmitters released from axon varicosities. The various functions of immune cells are modulated by released neurotransmitters without any direct synaptic contact between nerve endings and targeted immune cells requiring only functional neurotransmitter receptors on immune cells. Here, we briefly overview the role of the various receptor subtypes mediating nonsynaptic modulation of the function of immunocompetent cells both in the periphery and in the central nervous system.     

NMDA受体在痛觉过敏中的作用

N-甲基-D-天冬氨酸受体(NMDA受体)是中枢神经系统中兴奋性递质谷氨酸受体的一种类型,属于离子型受体。它涉及了体内许多复杂的生理和病理过程,包括wind-up、中枢敏化、长时程增强、外周敏化和内脏疼痛、细胞坏死和凋亡,除此以外,还参与了痛觉过敏的产生和维持。对NMDA受体在痛觉过敏中作用的探讨为研发新一代的镇痛药提供了广阔的思路和前景。     

Emerging Principles Governing Signal Transduction by Pattern-Recognition Receptors

The problem of recognizing and disposing of non-self-organisms, whether for nutrients or defense, predates the evolution of multicellularity. Accordingly, the function of the innate immune system is often intimately associated with fundamental aspects of cell biology. Here, we review our current understanding of the links between cell biology and pattern-recognition receptors of the innate immune system. We highlight the importance of receptor localization for the detection of microbes and for the initiation of antimicrobial signaling pathways. We discuss examples that illustrate how pattern-recognition receptors influence, and are influenced by, the general membrane trafficking machinery of mammalian cells. In the future, cell biological analysis likely will rival pure genetic analysis as a tool to uncover fundamental principles that govern host–microbe interactions.The innate immune system uses families of pattern-recognition receptors (PRRs) to recognize diverse microbial ligands (Janeway 1989; Janeway and Medzhitov 2002). During infection, these receptors provide signals that up-regulate general antimicrobial features of the innate immune system as well as instruct and initiate adaptive immunity (Iwasaki and Medzhitov 2010). A significant challenge faced by innate immune recognition is the reliable detection of highly diverse, rapidly evolving microbial organisms, many of which possess virulence mechanisms that enable survival within distinct host niches. Moreover, recognition must be linked to induction of contextual signals appropriate for the type of infection. The specificity, signal transduction, and cell biology of PRRs have evolved under these selective pressures to enable broad recognition of microbes within each host niche.Although the collection of PRRs is decidedly less diverse than antigen receptors of the adaptive immune system, the list of players has grown considerably over the past decade (Kawai and Akira 2010). If one classifies these receptors based on common structure and functional domains, then six families emerge: Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs), AIM-like receptors (ALRs), Nod-like receptors (NLRs), and OAS-like receptors (OLRs) (Geijtenbeek and Gringhuis 2009; Kawai and Akira 2010; Rathinam and Fitzgerald 2011; Lamkanfi and Dixit 2012; Kranzusch et al. 2013). Collectively, these receptors bind a diverse array of targets, including lipoproteins, polysaccharides, nucleic acids, carbohydrate structures, and a few highly conserved microbial proteins. These ligands are typically shared across large microbial classes, which facilitate broad recognition with such a limited number of PRRs. Moreover, alteration or masking of these ligands to avoid PRR activation often results in reduced microbial fitness.The molecular recognition challenge faced by PRRs is all the more complex when one considers the need to detect microbes within distinct subcellular niches. Microbes can be extracellular or intracellular within membrane-bound organelles, within the cytosol, or in the nucleus. In addition, both the innate and adaptive immune mechanisms appropriate for eliminating microbes within these distinct environments are quite distinct, so it is vital that PRR signaling communicate the location of a microbe as well its nature. We now understand that members of the PRR families highlighted above localize to distinct subcellular compartments, and, in some cases, localization can change in a dynamic fashion that regulates or influences recognition and signaling. Moreover, in some cases, signal transduction and resulting gene induction can be dramatically influenced by the organelle from which signaling initiates. Thus, the innate immune system has harnessed the organization inherent to cells as a means of achieving regulation and signaling specificity. Activation of PRRs can also feed back on basic cell biological processes, such as phagocytosis and autophagy, to enhance or accelerate the response to microbial infection.In the following sections, we discuss these links between cell biology and PRRs of mammalian innate immunity. Our discussions of PRR function and signal transduction will be limited to this theme, as a result, in part, of space constraints but also because in-depth reviews of each PRR family have appeared elsewhere. For discussion purposes, we have grouped the transmembrane PRRs together and the cytosolic PRRs together.     

Differential responses of regional sympathetic activity and blood flow to visceral afferent stimulation

The sympathetic nervous system is essential for the cardiovascular responses to stimulation of visceral afferents. It remains unclear how the reflex-evoked sympathetic output is distributed to different vascular beds to initiate the hemodynamic changes. In the present study, we examined changes in regional sympathetic nerve activity and blood flows in anesthetized cats. Cardiovascular reflexes were induced by either electrical stimulation of the right splanchnic nerve or application of 10 microg/ml of bradykinin to the gallbladder. Blood flows were measured using colored microspheres or the Transonic flow meter system. Sympathetic efferent activity was recorded from the left splanchnic, inferior cardiac, and tibial nerves. Stimulation of visceral afferents decreased significantly blood flows in the celiac (from 49 +/- 4 to 25 +/- 3 ml/min) and superior mesenteric (from 35 +/- 4 to 23 +/- 2 ml/min) arteries, and the vascular resistance in the splanchnic bed was profoundly increased. Consistently, stimulation of visceral afferents decreased tissue blood flows in the splanchnic organs. By contrast, activation of visceral afferents increased significantly blood flows in the coronary artery and portal vein but did not alter the vascular resistance of the femoral artery. Furthermore, stimulation of visceral afferents increased significantly sympathetic efferent activity in the splanchnic (182 +/- 44%) but not in the inferior cardiac and tibial nerves. Therefore, this study provides substantial new evidence that stimulation of abdominal visceral afferents differentially induces sympathetic outflow to the splanchnic vascular bed.     

秀丽隐杆线虫固有免疫功能神经调控机制研究进展

固有免疫系统是动植物个体应对外来微生物侵入感染时非常重要的抵御防线。秀丽隐杆线虫(Caenorhabditis elegans,简称线虫)作为研究宿主与病原菌之间相互作用的经典模式动物,近年来在神经和免疫之间相互作用的分子与遗传机制等方面的研究取得了长足进展。研究表明,线虫神经元通过释放神经递质与神经多肽(如多巴胺、NLP-20)等,激活相关信号通路途经,参与线虫对病原菌的识别、逃避、调节物理屏障防御能力和激活固有免疫反应,并表达分泌抗菌肽以清除病原菌等的调控进程。本文综述了线虫神经系统调控固有免疫功能机制的最新研究进展,为人们深入了解神经与免疫系统间相互作用的功能分子及其调控机制和揭示人类神经与免疫系统相关疾病的病理机理提供了重要信息。     

Systemic features of immune recognition in the gut

The immune system, to protect the body, must discriminate between the pathogenic and non-pathogenic microbes and respond to them in different ways. How the mucosal immune system manages to make this distinction is poorly understood. We suggest here that the distinction between pathogenic and non-pathogenic microbes is made by an integrated system rather than by single types of cells or single types of receptors; a systems biology approach is needed to understand immune recognition.     

Role of Neurochemicals in the Interaction between the Microbiota and the Immune and the Nervous System of the Host Organism

This work is concerned with the role of evolutionary conserved substances, neurotransmitters, and neurohormones, within the complex framework of the microbial consortium–immune system–nervous system axis in the human or animal organism. Although the operation of each of these systems per se is relatively well understood, their combined effects on the host organism still await further research. Drawing on recent research on host-produced and microbial low-molecular-weight neurochemicals such as biogenic amines, amino acids, and short-chain fatty acids (SCFAs), we suggest that these mediators form a part of a universal neurochemical “language.” It mediates the whole gamut of harmonious and disharmonious interactions between (a) the intestinal microbial consortium, (b) local and systemic immune cells, and (c) the central and peripheral nervous system. Importantly, the ongoing microbiota–host interactivity is bidirectional. We present evidence that a large number of microbially produced low-molecular-weight compounds are identical or homologous to mediators that are synthesized by immune or nervous cells and, therefore, can bind to the corresponding host receptors. In addition, microbial cells specifically respond to host-produced neuromediators/neurohormones because they have adapted to them during the course of many millions of years of microbiota–host coevolution. We emphasize that the terms “microbiota” and “microbial consortium” are to be used in the broadest sense, so as to include, apart from bacteria, also eukaryotic microorganisms. These are exemplified by the mycobiota whose role in the microbial consortium–immune system–nervous system axis researchers are only beginning to elucidate. In light of the above, it is imperative to reform the current strategies of using probiotic microorganisms and their metabolites for treating and preventing dysbiosis-related diseases. The review demonstrates, in the example of novel probiotics (psychobiotics), that many target-oriented probiotic preparations produce important side effects on a wide variety of processes in the host organism. In particular, we should take into account probiotics’ capacity to produce mediators that can considerably modify the operation of the microecological, immune, and nervous system of the human organism.