Figure 1

Hypothetical schematic of the roles of purine nucleotides and nucleosides in pain pathways. At sensory nerve terminals in the periphery, P2X₃ and P2X_2/3 receptors have been identified as the principal P2X purinoceptors present, although recent studies have also shown expression of P2Y₁ and possibly P2Y₂ receptors on a subpopulation of P2X₃ receptor-immunopositive fibers. Other known P2X purinoceptor subtypes (1--7) are also expressed at low levels in dorsal root ganglia. Although less potent than ATP, adenosine (AD) also appears to act on sensory terminals, probably directly via P1(A₂) purinoceptors; however, it also acts synergistically (broken black line) to potentiate P2X_2/3 receptor activation, which also may be true for 5-hydroxytryptamine, capsaicin, and protons. At synapses in sensory pathways in the CNS, ATP appears to act postsynaptically via P2X₂, P2X₄ and/or P2X₆ purinoceptor subtypes, perhaps as heteromultimers, and after breakdown to adenosine, it acts as a prejunctional inhibitor of transmission via P1(A₂) purinoceptors. P2X₃ receptors on the central projections of primary afferent neurons in lamina II of the dorsal horn mediate facilitation of glutamate and probably also ATP release. Sources of ATP acting on P2X₃ and P2X_2/3 receptors on sensory terminals include sympathetic nerves as well as endothelial, Merkel, and tumor cells. Yellow dots, molecules of ATP; red dots, molecules of adenosine. (Reproduced from [114] and modified from [105], used with permission from the American Physiological Society.)