ReviewIntercellular communication in sensory ganglia by purinergic receptors and gap junctions: Implications for chronic pain
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.
References (69)
- et al.
Purinoceptor-mediated calcium signaling in primary neuron-glia trigeminal cultures
Cell Calcium
(2008) - et al.
The effects of axotomy on neurons and satellite glial cells in mouse trigeminal ganglion
Pain
(2004) - et al.
Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain
Pain
(2005) Unexplained peculiarities of the dorsal rot ganglion
Pain
(1999)- et al.
Glial cell plasticity in sensory ganglia induced by nerve damage
Neuroscience
(2002) Satellite glial cells in sensory ganglia: from form to function
Brain Res. Rev.
(2005)- et al.
Aging is associated with an increase in dye coupling and in gap junction number in satellite glial cells of murine dorsal root ganglia
Neuroscience
(2006) - et al.
Ca2+-dependent exocytosis in the somata of dorsal root ganglion neurons
Neuron
(1996) The neural-glial purinergic receptor ensemble in chronic pain states
Trends Neurosci
(2010)- et al.
Peripheral inflammation upregulates P2X Receptor expression in satellite glial cells of mouse trigeminal ganglia: a calcium imaging study
Neuropharmacology
(2011)
Augmentation in gap junction-mediated cell coupling in dorsal root ganglia following sciatic nerve neuritis in the mouse
Neuroscience
Calcitonin gene-related peptide stimulation of nitric oxide synthesis and release from trigeminal ganglion glial cells
Brain Res.
Concurrent release of ATP and substance P within guinea pig trigeminal ganglia in vivo
Brain Res.
Endothelin immunoreactivity and mRNA expression in sensory and sympathetic neurones following selective denervation
Int. J. Dev. Neurosci.
Perikaryal surface specializations of neurons in sensory ganglia
Int. Rev. Cytol.
Are there functional P2X receptors on cell bodies in intact dorsal root ganglia of rats?
Neuroscience
Contribution of the activation of satellite glia in sensory ganglia to pathological pain
Neurosci. Biobehav. Rev.
Pain and purinergic signaling
Brain Res. Rev.
P2 receptors in satellite glial cells in trigeminal ganglia of mice
Neuroscience
Satellite cells surrounding axotomized rat dorsal root ganglion cells increase expression of GFAP-like protein
Neurosci. Lett.
Neuropathic pain: early spontaneous afferent activity is the trigger
Pain
Early blockade of injured primary sensory afferents reduces glial cell activation in two rat neuropathic pain models
Neuroscience
Change in excitability and phenotype of substance P and its receptor in cat Abeta sensory neurons following peripheral inflammation
Brain Res
Development of purinergic sensitivity in sensory neurons after peripheral nerve injury in the rat
Brain Res
Chemically mediated cross-excitation in rat dorsal root ganglia
J. Neurosci.
A comparative analysis of the activity of ligands acting at P2X and P2Y receptor subtypes in models of neuropathic, acute and inflammatory pain
Br. J. Pharmacol.
The participation of plasma membrane hemichannels to purinergic signaling
Biochim. Biophys. Acta [Epub ahead of print] PMID
Physiology and pathophysiology of purinergic neurotransmission
Physiol. Rev.
Activation of P2X7 receptors in glial satellite cells reduces pain through downregulation of P2X3 receptors in nociceptive neurons
Proc. Natl. Acad. Sci. U.S.A
Role of glia in orofacial pain
Neuroscientist
Potent block of Cx36 and Cx50 GJ channels by mefloquine
Proc. Natl. Acad. Sci. U.S.A
Tonabersat inhibits trigeminal ganglion neuronal-satellite glial cell signaling
Headache
Response to nerve injury in relation to neuropathic pain
Sodium channels in normal and pathological pain
Annu. Rev. Neurosci.
Cited by (96)
Insights into FcγR involvement in pain-like behavior induced by an RA-derived anti-modified protein autoantibody
2023, Brain, Behavior, and ImmunityThe potential role of CpG oligodeoxynucleotides on diabetic cardiac autonomic neuropathy mediated by P2Y12 receptor in rat stellate ganglia
2023, International ImmunopharmacologyInvolvement of Kir4.1 in pain insensitivity of the BTBR mouse model of autism spectrum disorder
2023, Biochimica et Biophysica Acta - Molecular Basis of Disease