Extracellular matrix mediated plasticity in neuropathic pain

In the nervous system, neurons and glial cells are embedded within an extracellular matrix (ECM), whose components not only provide structural support, but also regulate synapse formation and function, and modulate neuronal excitability. In the brain, ECM restricts synaptic and structural plasticity, and enzymatic digestion of ECM affects acquisition of memories, and promotes cognitive flexibility and extinction. In the pain pathway, matrix metalloproteinases (MMPs), the major ECM-digesting enzymes, are activated in neuropathic pain conditions to promote mechanical hypersensitivity; however, whether remodeling of spinal cord ECM contributes to pathological changes in dorsal horn nociceptive circuits and pain hypersensitivity remains unknown. We found that chronic inflammation and neuropathic pain lead to changes in the expression of ECM-related genes and to remodeling of the spinal ECM. To investigate the role of the ECM in restraining spinal plasticity, we injected chondroitinase ABC (chABC, an enzyme known to degrade ECM components) intrathecally before subjecting mice to Chronic Constriction Injury (CCI). Mice injected with chABC developed increased pain hypersensitivity as compared to that of vehicle-injected animals. Moreover, we found that Spared Nerve Injury (SNI) induces changes in spinal ECM chondroitin sulfate proteoglycans (CSPGs) such as Versican, Neurocan and Wisteria floribunda agglutinin (WFA)-binding proteins. In summary, our study demonstrates that peripheral nerve injury induces changes in the spinal ECM, suggesting a potential role of these modifications in the development of hypersensitivity.