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  • SNL in rats led to upregulated


    SNL in rats led to upregulated Panx1 mRNA and protein level in DRG but not in spinal cord, and immunostaining revealed increased Panx1 in DRG neurons [50]. Although it was not emphasized, Panx1 labeling in SGCs was also increased in this pain model. Intrathecal injection of Panx1 blockers or Panx1-specific siRNA reduced hypersensitivity induced by SNL. Using CCI and SNL pain models. Panx1 null mice were also found to be resistant to chronic pain [51]. In contrast to studies cited above [48], however, the authors found no protection when targeting deletion to either neurons or glia, but profound analgesia when inflammation was blocked by targeting Panx1 deletion to hematopoietic cells. This disagreement could have resulted from differential recombination in the two studies, and the finding of protection by deletion in hematopoetic crizotinib could reflect general suppression of inflammasome activation. Evidence summarized above that spinal cord GJs play a role in neuropathic pain emphasized analgesia produced by administration of GJ inhibitors. However, most of these drugs are even more potent on Panx1 channels, and tPanx1 blockers (CBX, probenecid and a peptide inhibitor) reduced hypersensitivity in a sural nerve transection neuropathic pain model [52]. This finding suggests that targeted blockade of spinal cord Panx1 might be effective for pain relief, although Panx1 expression in dorsal horn was not changed in this pain model, making it less likely that Panx1 is a key component of central pain sensitization. However, because delivery was intrathecal, blockers would be expected to act both on spinal cord and at DRG
    How does intercellular interaction affect pain? Intercellular signaling in the nervous system is mediated by the release of transmitters and by direct GJ-mediated ion and small molecule diffusion. For neurons, transmission speed is optimized through vesicular release and by axonal conduction. For non-neuronal cells, intercellular signals spread more slowly, mediated by regenerative release of Ca2+ from intracellular stores and diffusion of molecules. This mode of signal propagation has been termed the “calcium wave” and involves both GJs and chemical signaling, largely by ATP acting on P2 receptors. Such waves have been described both for astrocytes [53] and cultured sensory ganglia [54]. For this mechanism, Panx1 channels enable the release of ATP and likely also other transmitters, which then act on both ionotropic and metabotropic receptors to admit extracellular Ca2+ or release it from intracellular stores. We propose that the increased gap junction and Panx1 expression seen in sensory ganglia in the setting of chronic pain models play a determinant role in the hyperexcitability that is responsible for peripheral sensitization (Fig. 4). For GJs between SGCs, the role is to increase intercellular signal spread both within the envelopes that closely appose each neuron and also between neuron-SGC units. The GJs between SGCs and neurons and between neurons induced under painful states likely contribute to enhanced excitability, due either to exchange of second messengers or to a wave of depolarization accompanying the second messenger diffusion in SGCs. For Panx1, the role is likely enhanced ATP release from SGCs and/or neurons with activation of nearby neurons and SGCs. As noted above, injury enhances both Cx43 and Panx1 activity as a consequence of elevated extracellular K+ and intracellular Ca2+ [15], [55], [56], contributing to excitatory drive. A likely consequence of such activation is spread of Ca2+ signals from SGCs surrounding directly injured neurons to other SGCs (Fig. 4); to the extent that such activity achieves suprathreshold “cross excitation”, this recruitment could contribute to allodynia. Although changes in coupling and patterns of Ca2+ activation are less well understood in dorsal horn, it is likely that similar mechanisms could operate to provide local modulation at the point of convergence of peripheral sensory information.