P2X3 is a member of the P2X purinoceptor family of ATP-gated ion channels (98,99). Studies in rat, monkey, and mouse DRG have localized the expression of P2X3 receptors to small diameter primary afferent neurons (C-fibers) in DRG, usually those that bind the lectin Isolectin-B4 (43,117-125); functionally, P2X3-mediated currents have been detected in these same neurons (98,99,122,126-130). As such, P2X3 receptors have been strongly implicated in nociception and pain (94-99), although it should be noted that the majority of these studies have been performed in DRG that are devoid of colonic innervation (39,43). These data suggest that P2X3 receptors may play a role in the processing of nociceptive information through either homo-meric P2X3 channels or P2X2/3 heteromultimeric channels expressed either separately or together on individual neurons (98,99,124,127,131).
Activation of P2X3 receptors by ATP or the more selective agonist a,P-meATP evokes excitation of gastrointestinal afferents in the jejunum, gastroesophageal region, and colon (50,72,123,132). The proportion of afferents that respond to these agonists varies between different species and different regions of the gastrointestinal tract. In rat jejunum, a,P-meATP activates 100% of mesenteric afferents (132) whereas 89% of vagal tension receptors were activated in the guinea pig esophagus (50). By contrast, in the mouse esophagus, only 30% of mucosal and 43% of tension receptors respond to a,P-meATP (72), while no afferents in the ferret esophagus responded (133). Lower down the gastrointestinal tract, 65% of distension sensitive pelvic colonic afferents in the rat respond to ATP or a,P-meATP (123); in mouse colon, 40% of LSN serosal afferents responded to a,P-meATP compared with only 7% of pelvic nerve serosal afferents. A recent in vitro study in mouse showed that 40% of LSN afferents responded to a,P-meATP, which was reflected in the number of retrogradely labeled colonic thoracolumbar DRG neurons exhibiting P2X3-like immunoreactivity (LI) (134). Significantly fewer (7%) pelvic nerve afferents responded to a,P-meATP and only 19% of lumbosacral DRG neurons exhibited P2X3 immunoreactivity. Endogenous sources of ATP that may activate afferents are several, including enteric and sympathetic neurons, endothelial and inflammatory cells, and cell damage.
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