Role of microglia and P2X4 receptors in chronic pain

Pain plays an indispensable role as an alarm system to protect us from dangers or injuries. However, neuropathic pain, a debilitating pain condition caused by damage to the nervous system, persists for a long period even in the absence of dangerous stimuli or after injuries have healed. In this condition, pain becomes a disease itself rather than the alarm system and is often resistant to currently available medications. A growing body of evidence indicates that microglia, a type of macrophages residing in the central nervous system, play a crucial role in the pathogenesis of neuropathic pain. Whenever microglia in the spinal cord detect a damaging signal within the nervous system, they become activated and cause diverse alterations that change neural excitability, leading to the development of neuropathic pain. For over a decade, several lines of molecular and cellular mechanisms that define microglial activation and subsequently altered pain transmission have been proposed. In particular, P2X4 receptors (a subtype of purinergic receptors) expressed by microglia have been investigated as an essential molecule for neuropathic pain. In this review article, we describe our understanding of the mechanisms by which activated microglia cause neuropathic pain through P2X4 receptors, their involvement in several pathological contexts, and recent efforts to develop new drugs targeting microglia and P2X4 receptors.