Figure 8

Proposed hypotheses. (A) Scheme of the proposed hypothesis on the mechanisms by which p-ERK induces a pro-inflammatory phenotype in microglia and contributes to neuropathic pain. Peripheral nerve injury increases microglial p-ERK in spinal cord dorsal horn, which in turn leads to the expression of TNF and an increase in microglial motility. These pro-inflammatory microglia migrate towards the spinal injured neuron area attracted by chemoattractants, such as ATP/ADP. The enhancement of pro-inflammatory microglia sensitizes spinal nociceptive neurons by increasing the concentration of pro-algesic factors, such as TNF. (B) Scheme of the proposed hypothesis on the mechanisms by which CBR2 activation-induced MKP-3 promotes an anti-inflammatory phenotype in microglia and alleviates neuropathic pain. Microglial CBR2 are increased in microglia following peripheral nerve injury. Microglial CBR2 activation induces an anti-inflammatory phenotype in microglia by increasing MKP-3 expression, which selectively inhibits p-ERK in spinal cord dorsal horn. Subsequently, ERK dephosphorylation results in a reduction of TNF expression and microglial motility. The reduction in the migration of pro-inflammatory microglia reduces the source of pro-algesic factors, such as TNF preventing neuronal sensitization and alleviating peripheral nerve injury-induced allodynia.