Role of ion channels in mechanisms controlling gastrointestinal pain pathways

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Abstract

Hypersensitivity or sensitization of nociceptive primary afferents in the gastrointestinal tract has been proposed as a mechanism for organic and functional gastrointestinal pain. This hypersensitivity can be the result of alterations, either induced by a sensitizing agent or without a peripheral cause, in the functional properties of ion channels located in primary afferents. The tetrodotoxin-resistent sodium channel, known as Nav1.8, is present in nociceptive primary afferents, including those from the gut, and it has been implicated as being the main candidate for the enhanced activity that characterizes nociceptor sensitization. Other voltage-gated channels, such as calcium and potassium channels, can also contribute to the sensitization of primary afferents observed in gastrointestinal pain states.

Introduction

Gastrointestinal (GI) pain is one of the most prevalent forms of visceral pain and a sensory process of considerable clinical interest. Because of its clinical relevance, there is an enhanced interest in the physiopathology of GI pain from both academic and industrial research institutions. Understanding the mechanisms of GI pain and gaining new knowledge about its pharmacology can provide new approaches for its treatment.

There are essentially two forms of GI pain: organic and functional. Organic GI pain is a well-understood phenomenon that correlates closely with the presence of a lesion in the GI tract or in the nerves that transmit information from the gut to the central nervous system (CNS). Organic GI pain is usually the consequence of a traumatic, inflammatory or degenerative lesion of the gut, or is produced by tumours that impinge on its sensory innervation. This kind of GI pain can be traced to a clear originating cause in the periphery. The pain is attributable to the peripheral lesion, which causes a hypersensitivity (sensitization) of the local sensory afferents, and to the processing of these enhanced signals by CNS mechanisms that amplify and maintain an increased excitability of central neurons 1., 2., 3.. The latter mechanism is usually referred to as ‘central sensitization’ by analogy to the well-known peripheral sensitization of nociceptive afferents.

More intriguing is the other form of GI pain, known as ‘functional’ abdominal pain. This is pain in the absence of demonstrable pathology of the gut or its associated nerves. Patients complain of discomfort, bloating or pain but, after extensive clinical investigations, nothing is found in the GI tract that could explain the sensory symptoms. Functional GI pain is the central symptom of irritable bowel syndrome, a condition characterized by discomfort, pain and alterations of defecation in the absence of peripheral pathology [4]. Functional GI pain is commonly interpreted as a consequence of hypersensitivity of GI nociceptive pathways, either of the sensory receptors in the gut or of the central neurons 5., 6.. In this case, the sensitization of the nociceptive pathway is the mechanism for the enhanced pain perception even though the sensitizing process does not involve a demonstrable lesion in the gut.

The process of enhanced sensitivity or sensitization, either peripherally or centrally, is therefore at the heart of all current interpretations of the physiopathology of GI pain. In the case of organic pain, peripheral sensitizing agents include inflammatory mediators and cytokinins released at the injury site. In addition, there are contributions from neuromodulators released by the sensory endings activated by the noxious stimuli, a process known as neurogenic inflammation. Central sensitization of CNS neurons is triggered by the enhanced activity of the sensory afferents and is maintained by the properties of the neural network and by the neurotransmitters released by the activated neurons. The same mechanisms, peripheral and/or central, have been proposed to apply in the case of functional GI pain, with the proviso that there should be no peripheral trigger to the process.

Sensory innervation of the gut not only has a role in pain perception but also participates in the regulation and control of GI motility and secretion [7]. Therefore, any alteration in the excitability of sensory afferents will have a direct influence on the regulatory functions of the gut. Often, clinical symptoms associated with GI lesions are the consequence of hypersecretion or hypermotility caused by sensitized GI afferents. Alternatively, mediators released at the periphery by inflammation, either neurogenic or non-neurogenic, can change the properties of the secretory and motor cells which, in turn, will affect the sensory signals arising from the inflamed area. Therefore, it is almost impossible to separate the sensory alterations caused by peripheral GI lesions from the motor and secretory disturbances also resulting from the lesion.

The main focus of this article is the process of sensitization of GI nociceptive pathways. We have addressed the role of voltage-gated ion channels in the triggering and maintenance of sensitization of GI sensory afferents, which is likely to be exerted mainly through control of action potential generation. Other recent reviews have addressed the pharmacology of GI nociceptive pathways [8] and the sensory innervation of the GI tract [7] in detail. Here, we consider only the sensitization of GI primary afferents and the role of voltage-gated ion channels in this process.

Section snippets

Sodium channels

Voltage-gated sodium channels are crucial for the propagation of action potentials along axons and also contribute to controlling membrane excitability. There are several voltage-gated sodium channel subtypes expressed in primary sensory neurons. The sodium currents that they mediate are most easily classified electrophysiologically into two types on the basis of their sensitivity to a natural toxin, tetrodotoxin (TTX). All spinal ganglion neurons express TTX-sensitive sodium currents, but

Calcium channels

In contrast to the large body of recent work on the role of sodium channels in visceral pain sensation, relatively little is known about the participation of voltage-gated calcium channels. However, there are data indicating that calcium channels may be important for some aspects of GI nociceptive afferent functioning. For example, characterization of the biophysics of identified colon neurons [18] showed that the majority of these neurons expresses a persistent calcium current of relatively

Potassium channels

The excitability of primary afferents is also influenced by the expression of voltage-gated potassium channels in the membrane. A reduction in the density of potassium channels produces an increase in excitability, and this type of effect has been described in presumed nociceptive neurons isolated from spinal ganglia innervating the inflamed urinary bladder [30]. In these experiments, the peak density of an A-type potassium current was significantly smaller in neurons innervating the inflamed

Conclusions

Sensitization of primary afferent nociceptive neurons is clearly a substrate for organic GI pain and a potential mechanism for functional pain states. The latter remains a hypothetical proposal in the absence of direct evidence linking functional abdominal pain with primary afferent sensitization. Central amplification of peripheral signals and other CNS mechanisms of potential dysfunctions are also important components of both organic and functional GI pain states.

Sensitization of GI

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The work from the authors’ laboratory, described in this review, was supported by the Madrid Regional Government (Contrato Programa) and the Ministry of Science and Technology of Spain (SAF-2000-0199).

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