Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat

• Chemotherapy causes mechanical hypersensitivity and activated astrocytes.
• Microglia were not activated by chemotherapy but were by spinal nerve ligation.
• Astrocyte activation and mechanical sensitivity were prevented with minocycline.

Spinal microglia are widely recognized as activated by and contributing to the generation and maintenance of inflammatory and nerve injury related chronic pain; whereas the role of spinal astrocytes has received much less attention, despite being the first glial cells identified as activated following peripheral nerve injury. Recently it was suggested that microglia do not appear to play a significant role in chemotherapy-induced peripheral neuropathy (CIPN), but in contrast astrocytes appear to have a key role. In spite of the generalizability of astrocyte recruitment across chemotherapy drugs, its correlation to the onset of the behavioral CIPN phenotype has not been determined. The astroglial and microglial markers glial fibrillary acidic protein (GFAP) and OX-42 were imaged here to examine glial reactivity in multiple models of CIPN over time and to contrast this response to that produced in the spinal nerve ligation (SNL) model. Microglia were strongly activated following SNL, but not activated at any of the time points observed following chemotherapy treatments. Astrocytes were activated following both oxaliplatin and bortezomib treatment in a manner that paralleled chemotherapy-evoked behavioral changes. Both the behavioral phenotype and activation of astrocytes were prevented by co-administration of minocycline hydrochloride in both CIPN models, suggesting a common mechanism.