Elsevier

Brain Research

Volume 1487, 3 December 2012, Pages 183-191
Brain Research

Review
Intercellular communication in sensory ganglia by purinergic receptors and gap junctions: Implications for chronic pain

https://doi.org/10.1016/j.brainres.2012.03.070Get rights and content

Abstract

Peripheral injury can cause abnormal activity in sensory neurons, which is a major factor in chronic pain. Recent work has shown that injury induces major changes not only in sensory neurons but also in the main type of glial cells in sensory ganglia—satellite glial cells (SGCs), and that interactions between sensory neurons and SGCs contribute to neuronal activity in pain models. The main functional changes observed in SGCs after injury are an increased gap junction-mediated coupling among these cells, and augmented sensitivity to ATP. There is evidence that the augmented gap junctions contribute to neuronal hyperexcitability in pain models, but the mechanism underlying this effect is not known. The changes in SGCs described above have been found following a wide range of injuries (both axotomy and inflammation) in somatic, orofacial and visceral regions, and therefore appear to be a general feature in chronic pain. We have found that in cultures of sensory ganglia calcium signals can spread from an SGC to neighboring cells by calcium waves, which are mediated by gap junctions and ATP acting on purinergic P2 receptors. A model is proposed to explain how augmented gap junctions and greater sensitivity to ATP can combine to produce enhanced calcium waves, which can lead to neuronal excitation. Thus this simple scheme can account for several major changes in sensory ganglia that are common to a great variety of pain models.

Section snippets

Introduction, a brief survey of sensory ganglia

Sensory ganglia contain the cell bodies of sensory neurons, which have a bifurcating axon, with one branch going to the periphery, and the other projects into the dorsal horn of the spinal cord. The two main types of sensory ganglia are the dorsal root ganglia (DRG), which innervate most of the body, including internal organs, and the trigeminal ganglia (TG), which innervate the head, face and teeth. The traditional view has been that the main role of the neuronal somata in these ganglia is

Satellite glial cells in sensory ganglia

Sensory neurons are surrounded by specialized glial cells known as ‘satellite glial cells’ (SGCs), and recent work indicates that these cells must be taken into consideration when discussing cellular interactions in sensory ganglia. Satellite glial cells are unique in that they usually form a sheath around individual neurons, which is tight, but still permeable to large molecules (for a review see Hanani, 2005). Fig. 1 shows a low power electron micrograph of a sensory neuron and its SGC

The effect of injury on SGCs

Research on sensory ganglia has been largely motivated by the need to understand their role in chronic pain and has focused on the changes in sensory neurons following injury. The most striking functional changes observed in sensory neurons in a variety of pain models in animals are the increased excitability and spontaneous electrical activity (Devor, 2006). This augmented excitability is a major factor in chronic pain because increased firing in these cells would activate neurons in the

Do gap junctions contribute to chronic pain?

The available information indicates that augmented gap junctions contribute to chronic pain in a variety of pain models. We showed in in vitro studies that blocking gap junctions reduced the spontaneous electrical activity and hyperexcitability of sensory neurons (Dublin and Hanani, 2007, Huang et al., 2010). The fact that the experiments were done on isolated ganglia supports the idea that the neuronal somata themselves can generate abnormal electrical activity. Gap junction blockers inhibited

Purinergic receptors in sensory neurons

Receptors for ATP (P2 purinergic receptors—P2Rs) consist of two main subtypes: ionotropic (P2XRs) and metabotropic (P2YRs). There are seven subtypes of P2XRs (1–7) and eight subtypes of P2YRs (1,2,4,6,11–14), for a review see Burnstock (2007). There is strong evidence that ATP plays an important role in neuron-glia signaling and in pain mechanisms and there have been numerous investigations on the pharmacology of P2Rs in the pain pathways (Fields and Burnstock, 2006, Burnstock, 2007, Andó et

Purinergic receptors in SGCs

Using calcium imaging, Weick et al. (2003) showed that SGCs in mouse TG possess functional P2YRs, which were further classified as P2Y1,2,4,6,12,13Rs (Ceruti et al., 2008, Weick et al., 2003). In vitro incubation with the proinflammatory peptide bradykinin, increased SGC response to P2YR stimulation (Ceruti et al., 2008). There is evidence for the presence of P2X7R in SGCs in rodent (Zhou et al., 2001, Kushnir et al., 2011) and human DRG (Chessell et al., 2005). As sensory neurons can release

Intercellular calcium waves (ICWs)

When a single astrocyte is stimulated there is an increase in [Ca2+]in in that cell, which is followed by elevated [Ca2+]in in neighboring astrocytes. This phenomenon is termed ICWs and it provides astrocytes with a means for long-range (albeit slow) signaling (Scemes and Giaume, 2006). The propagation of ICWs depends on both gap junction-mediated diffusion between coupled cells of second messengers such as IP3, and by the release of ATP that diffuses through extracellular space, interacting

A preliminary model to explain how P2R and gap junction upregulation can cause chronic pain

Chronic pain is a result of numerous factors (Gold and Gebhart, 2010) and there is no single theory that can encompass all its causes and manifestations. Still, simple models attempting to explain a set of observations can help in asking questions and advancing our understanding of this topic. The scheme shown in Fig. 5 explains how augmented gap junctions and greater sensitivity to ATP can lead to abnormal neuronal activity in injured and non-injured neurons. The main assumption underlying

Conclusion

In a comprehensive review on nociceptor sensitization in the pathogenesis of pain, Gold and Gebhart (2010) highlighted the large variety of receptors and biochemical pathways that underlie pain, which complicates the search for effective pain therapy. For example, the heterogeneity of mechanoreceptors is likely to frustrate any effort to block such receptors selectively. These authors reached the conclusion that there is, at least currently, no generalized way to approach the question of

Acknowledgments

Work done in the author’s laboratory was supported by the European Community’s Seventh Framework Programme through the Marie Curie Initial Training Network Edu-GLIA, the Israel Cancer Association, the Israel Science Foundation (Grant no. 212/08), by the US–Israel Binational Science Foundation (Grant no. 2007311) and by the Hebrew University Center for Pain Research.

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