A. Spontaneous and distension-induced activity in ureter afferent fibres. Multifibre afferent responses to rapid distension. Note that background afferent activity occurs in bursts and that ureter distension results in an initial burst of discharge (circle) followed by a phase of maintained activity (bar). B. ATP can sensitise ureter afferent fibres. An example representative of distension-induced afferent activity before and following intraluminal application of increasing concentrations of ATP. c. TNP-ATP inhibits distension-induced afferent activity. A multifibre recording to show distension-induced afferent activity in control and in the presence of TNP-ATP. (Reproduced from [33], with permission of Elsevier.)

A. ATP concentration ([ATP]) in perfusate immediately before and after distension of the human ureter, grouped in pressure ranges. The mean [ATP] after distension is significantly greater than before distension in each pressure range P < 0.01; n = 7, error bars represent s.e.m. (Reproduced from [35], with permission from Springer.) B. ATP concentration in luminal fluid samples from normal and inflamed rat colorectum during distension. Values are means ± SE. (Reproduced from [67] and used with permission from the American Physiological Society.)

A. Schematic representation of hypothesis for purinergic mechanosensory transduction in tubes (e.g., ureter, vagina, salivary and bile ducts, gut) and sacs (e.g., urinary and gall bladders, lung). It is proposed that distension leads to release of ATP from epithelium lining the tube or sac, which then acts on P2X₃ and/or P2X_2/3 receptors on subepithelial sensory nerves to convey sensory/nociceptive information to the CNS. (Reproduced from [5], with permission from Blackwell.) B. schematic of a novel hypothesis about purinergic mechanosensory transduction in the gut. It is proposed that ATP released from mucosal epithelial cells during moderate distension acts preferentially on P2X₃ and/or P2X_2/3 receptors on low-threshold subepithelial intrinsic sensory nerve fibers (labelled with calbindin) to modulate peristaltic reflexes. ATP released during extreme (colic) distension also acts on P2X₃ and/or P2X_2/3 receptors on high-threshold extrinsic sensory nerve fibers [labelled with isolectin B4 (IB4) or are peptidergic] that send messages via the dorsal root ganglia (DRG) to pain centres in the CNS. (Reproduced and modified from [115], published by John Wiley and Sons, Inc.)

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.)