Activated microglia nibbling glycosaminoglycans from spinal cord perineural nets: a new mechanism for neuropathic pain

In a recent study published in Science , 1 Tansley, Khoutorsky et al. unraveled a novel mechanism by which activated microglia can induce pain and pain hypersensitivity. It involves the degradation of perineural nets (PNNs) around neurons in the spinal cord dorsal horn lamina I (Fig. 1 ). Fig. 1 a Development of neuropathic pain by peripheral nerve injury, which leads to microglia activation in the spinal cord. b Activated microglia degrade perineural nets (PNNs) of nerves in the spinal cord dorsal horn lamina I leading to acute pain and the development of long-lasting pain hypersensitivity (allodynia). This effect of microglia can be imitated by chondroitinase treatment. In the present study, chondroitinase ABC (systematic name: chondroitin ABC lyase) was employed, a bacterial enzyme from Proteus vulgaris , that degrades polysaccharides such as chondroitin 4-sulfate and chondroitin-6-sulfate producing disaccharides. It cleaves off the side chains of chrondroitin sulfate proteoglycans. Treatment with this enzyme has previously been proposed for the treatment of spinal injuries. Chondroitin sulfate proteoglycans are glycoproteins to which chondroitin sulfate side chains are attached. They are secreted from cells and have various functions. For example, they inhibit axon regeneration after spinal cord injury. c Glycosaminoglycans (GAGs, also termed mucopolysaccharides) are linear, acidic polysaccharides that are composed of disaccharide units, an uronic acid (mostly glucuronic acid) which forms a 1,3-glycoside linkage with an amino sugar (e.g. N -acetylglucosamine). Chondroitin sulfate is a sulfated polysaccharide consisting of disaccharide units of D -glucuronic acid (or <10% L -iduronic acid) and N -acetylgalactosamine. It contains about 1 sulfate per disaccharide. The figure has been created with BioRender.com Full size image

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