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Satellite glial cells (SGCs) closely envelop cell bodies of neurons in sensory, sympathetic and parasympathetic ganglia. This unique organization is not found elsewhere in the nervous system. SGCs in sensory ganglia are activated by numerous types of nerve injury and inflammation. The activation includes upregulation of glial fibrillary acidic protein, stronger gap junction-mediated SGC–SGC and neuron–SGC coupling, increased sensitivity to ATP, downregulation of Kir4.1 potassium channels and increased cytokine synthesis and release. There is evidence that these changes in SGCs contribute to chronic pain by augmenting neuronal activity and that these changes are consistent in various rodent pain models and likely also in human pain. Therefore, understanding these changes and the resulting abnormal interactions of SGCs with sensory neurons could provide a mechanistic approach that might be exploited therapeutically in alleviation and prevention of pain. We describe how SGCs are altered in rodent models of four common types of pain: systemic inflammation (sickness behaviour), post-surgical pain, diabetic neuropathic pain and post-herpetic pain.

SUMMARY Primary sensory neurons in the DRG play an essential role in initiating pain by detecting painful stimuli in the periphery. Tissue injury can sensitize DRG neurons, causing heightened pain sensitivity, often leading to chronic pain. Despite the functional importance, how DRG neurons function at a population level is unclear due to the lack of suitable tools. Here we developed an imaging technique that allowed us to simultaneously monitor the activities of >1,600 neurons/DRG in live mice and discovered a striking neuronal coupling phenomenon that adjacent neurons tend to activate together following tissue injury. This coupled activation occurs among various neurons and is mediated by an injury-induced upregulation of gap junctions in glial cells surrounding DRG neurons. Blocking gap junctions attenuated neuronal coupling and mechanical hyperalgesia. Therefore, neuronal coupling represents a new form of neuronal plasticity in the DRG and contributes to pain hypersensitivity by “hijacking” neighboring neurons through gap junctions.

Background: Chemotherapy-induced peripheral neuropathy is a serious side effect in cancer treatment, a major manifestation being neuropathic pain that can be debilitating and can reduce the quality of life of the patient. Oxaliplatin and taxol are common anti-cancer drugs that induce neuropathic pain by an unknown mechanism. We tested the hypothesis that satellite glial cells in dorsal root ganglia (DRGs) are altered in chemotherapy-induced peripheral neuropathy models and contribute to neuropathic pain. Methods: Mice were injected with either oxaliplatin or taxol and examined at 7-30 days. Glial fibrillary acidic protein (glial activation marker) expression was determined by immunohistochemistry. Satellite glial cells in isolated DRG were injected with the fluorescent dye Lucifer yellow and the incidence of dye coupling among these cells that surround different neurons was quantified. Results: Taxol or oxaliplatin increased glial fibrillary acidic protein expression in satellite glial cells. Gap junction-mediated coupling between satellite glial cells was increased by up to fivefold after oxaliplatin and by up to twofold after taxol. This is consistent with work on other pain models showing that augmented satellite glial cell coupling contributes to chronic pain. Administration of the gap junction blocker carbenoxolone to chemotherapy-treated mice produced an analgesic-like effect. Conclusions: We propose that increased coupling by gap junctions is part of satellite glial cell activation, and that augmented coupling contributes to the lowering of pain threshold in oxaliplatin-and taxol-treated mice. We further propose that gap junction blockers may have potential in treating chemotherapy-induced neuropathic pain.

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