The contribution of satellite glial cells to chemotherapy‐induced neuropathic pain

Abstract

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.

Spinal sample showing p-JNK and P38 associated with the pain signaling transduction of glial cell in neuropathic pain

“…In our experiments, we also found that both spinal astrocytes and satellite cells 17 surrounding the dorsal ganglion neurons are activated, markedly enhancing GFAP expression. The interaction between satellite glial cells and dorsal ganglion neurons in the ganglion provides new ideas for further studies.…”

The Development and Maintenance of Paclitaxel-induced Neuropathic Pain Require Activation of the Sphingosine 1-Phosphate Receptor Subtype 1

“…Likewise, accumulating evidence implicates neuroinflammatory processes in the alteration of glia-neuronal communication in the dorsal horn of the spinal cord that is associated with paclitaxel-induced neuropathic pain. Specifically, hyperactivation of glial cells (45,76,77), enhanced TNF-␣ and IL-1␤ (45,78,79), and nitroxidative species production (45) as well as dysregulation of glutamate homeostasis (45,80,81) have been documented. A recent study revealed that increased activation of GSK-3␤ in spinal cord contributes to the development and maintenance of paclitaxelinduced neuropathic pain by activating astrocytes and causing the overproduction of IL-1␤ (79).…”

Expression of gap junctions bearing connexin-43 subunits and glial fibrillary acidic protein in the rat dorsal root ganglia following hind paw incision

“…Oxaliplatin and taxol were able to increase the gap junctions between the satellite glial cells by up to five folds. 22 The earlier authors also noted that submandibular inflammation results into the increased signaling between the satellite cells themselves and also with the neurons. Furthermore, this signaling decreased after administration of carbenoxolone, a well-established gap junctional blocker.…”

“…It is also proposed that inflammation induces augmented cell coupling in DRGs that contributes to neuronal hyperexcitability leading to visceral pain. 22 …”