Neuropathic pain and purinergic receptors: Involvement of microglia

Microglia play an important role as immune cells in the central nervous system. Neuropathic pain is often a consequence of nerve injury due to surgery, bone compression, cancer, diabetes or infection. Recently, accumulating evidence indicates the important role that ATP receptors expressed on activated microglia have in neuropathic pain. Activated microglia show a progressive series of changes in morphology, gene expression, function and number, and produce and release various chemical mediators, including proinflammatory cytokines. The expression of the P2X₄ receptor, a subtype of ATP receptors is enhanced in spinal microglia in a peripheral nerve injury model, and blocking pharmacologically and suppressing P2X₄ receptor gene expression reduces the neuropathic pain. Several cytokines such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) in the dorsal horn are also increased after nerve lesion and have been implicated in contributing to nerve-injury pain. ATP can activate mitogen-activated protein kinase (MAPK) leading to the release of bioactive substances including cytokines from microglia. These diffusible factors from activated microglia may have an important role in the development of neuropathic pain through the stimulation of purinergic receptors.