Gap junctions, pannexins and pain

Abstract

Enhanced expression and function of gap junctions and pannexin (Panx) channels have been associated with both peripheral and central mechanisms of pain sensitization. At the level of the sensory ganglia, evidence includes augmented gap junction and pannexin1 expression in glial cells and neurons in inflammatory and neuropathic pain models and increased synchrony and enhanced cross-excitation among sensory neurons by gap junction-mediated coupling. In spinal cord and in suprapinal areas, evidence is largely limited to increased expression of relevant proteins, although in several rodent pain models, hypersensitivity is reduced by treatment with gap junction/Panx1 channel blocking compounds. Moreover, targeted modulation of Cx43 expression was shown to modulate pain thresholds, albeit in somewhat contradictory ways, and mice lacking Panx1 expression globally or in specific cell types show depressed hyperalgesia. We here review the evidence for involvement of gap junctions and Panx channels in a variety of animal pain studies and then discuss ways in which gap junctions and Panx channels may mediate their action in pain processing. This discussion focusses on spread of signals among satellite glial cells, in particular intercellular Ca²⁺ waves, which are propagated through both gap junction and Panx1-dependent routes and have been associated with the phenomenon of spreading depression and the malady of migraine headache with aura.

Keywords: Cx43; DRG; GJ: Panx1; Ganglia; Satellite glial cell; Sensory neuron; Spinal cord; TG.

Figure 1

Peripheral and central pathways of pain. Nerve fibers (labeled red, blue and green) innervate skin and other organs. The cell bodies of these sensory neurons are surrounded by Satellite Glial Cells (SGCs, gray encircling neuron somata) located in sensory ganglia, and for most body areas the neurons are in dorsal root ganglia (DRG). Sensory axons form their first synapses in the dorsal horn of the spinal cord. From here, post-synaptic neurons cross the spinal cord and are relayed via ascending tracts to central areas (brainstem, thalamus, cortex).

Figure 2

Cross-excitation in sensory ganglia, in which excitation spreads from one excited sensory neuron to depolarize another. This figure depicts one of several ways in which this phenomenon has been demonstrated. A. Brief tetanic electrical stimulation is applied to a nerve root containing the red but not either blue or green axon, and a microelectrode records intracellularly from the blue neuron while repeatedly applying subthreshold current pulses. As in Fig. 1 gray semicircles around neurons are SGCs, which are interlinked to one another via gap juncitons (GJs); stimulated neuron releases K⁺ and it and SGCs release ATP. B. Electrical recordings from the neuron during this experiment. Lower recording shows neuron response to tetanic stimulation, while recordings labeled 1–3 correspond to responses to neuron depolarization at selected times. 1) Subthreshold neuron depolarization does not generate an action potential in the neuron. 2) During nerve stimulation, which slightly depolarizes the neuron as indicated in the lower recording, the current pulse in the neuron sums with the small depolarization due to nerve stimulation to fire action potentials. 3) The small depolarization due to nerve stijmulation declines and no longer is sufficient to reach threshold in the neuron. Modified from [5].

Figure 3

Hypothesized roles of GJs and Panx1 in intercellular communication in sensory ganglia. A. Under normal conditions, SGCs surrounding each neuron (N1, N2) are coupled to one another weakly but not to SGCs of neighboring sheaths. B. When neuron N1 (red) is activated/injured, K⁺ is released which sustains neuronal depolarization and activates Panx1 channels to release other signaling molecules including ATP. ATP binds with receptors (P2X7 receptors, located only in SGCs, are illustrated as blue symbols, but other P2X ionotropic and P2Y metabotropic receptors are located on both neurons and glia, providing positive feedback). Gap junctions are strengthened between SGCs (white bars linking yellow SGCs surrounding individual neurons and turquoise between SGCs surrounding different SGCs), between neurons and glia (green bars) and, in lower number, between neurons. In addition, neurons and SGCs become hyper-responsive to purinergic stimulation (not illustrated).

Figure 4

Model of GJ and Panx1 roles in intercellular communication in sensory ganglia and likely other neural pain processing centers. DRG is illustrated here as a matrix of circular neurons surrounded by gray SGCs. A. When they are injured, neurons within sensory ganglia become active (red). B. Excitation spreads from neurons to their surrounding SGCs, indicated by the local SGCs becoming yellow, as a result of ATP released by Panx1 and acting on P2 receptors and also GJ mediated signal spread. C. With prolonged stimulation, signals such as Ca²⁺ waves are relayed between SGCs surrounding adjacent neurons. D. Ultimately, additional neurons (pink) are recruited into the neural response, likely contributing to the phenomenon of allodynia.