Role of neuron-satellite glia cell signaling in pelvic pain and visceral cross-sensitization

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Abstract Millions of people suffer from chronic pelvic pain that is often associated with interstitial cystitis/bladder pain syndrome (IC/BPS) and irritable bowel syndrome (IBS). Several factors have been implicated in the pathophysiology of these disorders but mechanisms underlying pain chronification are still poorly understood. This proposal is motivated by our previous studies characterizing neuron-glial interactions in sensory ganglia and demonstrating their importance in chronic pain models involving orofacial and hindlimb inflammation. Based on these findings, we focus on neural integration processes that occur within the sensory ganglia (dorsal root ganglia: DRG) that innervate pelvic organs, and investigate whether and to what extent altered intercellular signaling between DRG sensory neurons and satellite glial cells (SGCs) provides a common mechanism in bladder and colon pain. Moreover, we propose that such neuron-glia interactions may contribute to pelvic organ crosstalk that underlies the known comorbidity of IC/BPS and IBS. We have shown that neurons in sensory ganglia are in close spatial and functional contact with SGCs. SGCs support neuronal homeostasis but also respond to neuronal stimulation through release of “gliotransmitters” and other chemical mediators, such as ATP and cytokines, which modulate neuronal excitability. There is strong evidence that activation of glia in the CNS and PNS play key roles in development and maintenance of pain, and the importance of the crosstalk between SGCs and neurons in pathological pain is becoming increasingly evident. Little is still known, however, of whether and to what extent the crosstalk between SGCs and neurons contributes to pelvic organ sensitization and cross-sensitization, and through which mechanisms SGC-neuron signaling may be enhanced and thereby contribute to pelvic pain. We have shown that in experimental colitis, gap junction (GJ) mediated neuron-SGC signaling is enhanced in the DRG innervating the colon. Moreover, findings from our studies with deletion of P2X7 receptors and pannexin 1 (Panx1) channels, main molecular mediators of SGC-neuron signaling, suggest that enhanced SGC-neuron communication through activation of the P2X7R-Panx1 complex plays a key role in development of DRG hyperexcitability and tactile hypersensitivity. Based on these findings, we hypothesize that intercellular GJ and P2X7R-Panx1 mediated signaling in the DRG play a key role in sensitization of pelvic afferents by contributing mechanisms that enhance SGC activation and neuronal excitability and can contribute to colon-bladder cross-sensitization. To test this hypothesis, we will employ well established models of direct bladder and colon insult, and combined behavioral, functional and molecular approaches using wildtype and transgenic mice with global or cell-specific deletion of Cx43, Panx1 and P2X7R. Findings from these studies are expected to demonstrate the key role of pathologically enhanced SGC-neuron signaling in the development of pelvic pain and visceral cross-sensitization, and reveal that gap junctions and the P2X7R-Panx1 functional complex drive the enhanced SGC-neuron intercellular signaling in this process, providing novel therapeutic targets for future clinical translation.