, 2010). A similar situation pertains in the intestine, where ATP and αβmeATP directly excite mesenteric afferents running from the

wall of the small intestine in the rat ( Kirkup et al., 1999). Action potential discharge in pelvic nerve afferent fibers elicited by colon distension are much attenuated in P2X3 knockout mice ( Shinoda et al., 2009; Wynn et al., 2003). These observations all point to a role for ATP acting directly to excite primary afferent nerves in physiological and probably pathological circumstances. Pain. Interest in P2X receptors and pain dates from early observations that ATP itself evokes pain when applied to blisters ( Bleehen et al., 1976). This is likely mediated by activation of P2X3 subunits, which are restricted in their distribution to a subset of primary afferent neurons ( Chen et al., 1995; Lewis et al., 1995) Perifosine manufacturer that also express receptors for capsaicin (TRPV1) and isolectin B4 ( Guo et al., 1999; Vulchanova et al., 1998). The relevance of this observation to any role in chronic inflammatory or neuropathic pain

remains less clear, however. P2X3 knockout mice do have an afferent phenotype, most notably reduced mechanical allodynia ( Cockayne et al., 2000), and antagonists selective for receptors containing P2X3 subunits ( Jarvis et al., 2002) reduce chronic neuropathic and inflammatory pain in the rat. Local administration of the P2X2/3 antagonist A-317491, or prior depletion

of P2X3 receptor expression isothipendyl by intrathecal antisense oligonucleotides, also reduce the mechanical hyperalgesia evoked by carageenan ( Oliveira et al., http://www.selleckchem.com/products/Vorinostat-saha.html 2009) or complete Freund’s adjuvant ( Ballini et al., 2011). This is consistent with a role for ATP acting on peripherally situated P2X2/3 receptors, as a component of a local “inflammatory soup. Selective P2X3 receptor antagonists can prevent the mechanical allodynia seen in neuropathic pain models, whether applied locally or intrathecally (Gum et al., 2012; McGaraughty et al., 2003). Locally, this is associated with sensitization (an increased in expression of membrane P2X3 receptors) rather than increased ATP release (Chen et al., 2005). Cochlea. Several cells types in the cochlea express P2X receptors, and their functional roles have been comprehensively reviewed ( Housley et al., 2009). The most compelling is that part played by ATP released from Köllicker’s organ. This organ (also known as the greater epithelial ridge) consists of columnar supporting cells, and it is prominent in the neonatal cochlea before the onset of hearing. At this developmental stage, ATP is released from the supporting cells in bursts and depolarizes the adjacent inner hair cells, causing them to fire bursts of action potentials which, in turn, excites auditory nerves through release of glutamate ( Tritsch and Bergles, 2010; Tritsch et al., 2007).