It provides the primary excitatory stimulus to the auditory nerve during this period, and this is responsible for the downstream survival and maturation of auditory neurons. Retina. An extensive literature pertains to P2X receptor expression in the retina, both in neurons and in supporting cells ( Housley et al., 2009). The speculation around their roles in normal function or disease currently lacks insight at the cellular level, but this is clearly an area worth Stem Cell Compound Library exploring. Recently, it has been proposed that central P2X4 receptors are involved in neuropathic pain (Trang and Salter, 2012). The key evidence here is that removal of P2X4 receptors strikingly prevents the development of mechanical allodynia following

peripheral nerve injury (Tsuda et al., 2003, www.selleckchem.com/products/carfilzomib-pr-171.html 2009; Ulmann et al., 2008). Peripheral nerve injury is followed by activation of spinal microglia. It is suggested that ATP acting on P2X4 receptors drives the release of BDNF from spinal microglia, and that this in turn is critical for the rewiring that

underlies the perception of mild tactile stimuli as noxious. The neuronal subtypes and specific microcircuitry involved remain to be elucidated. P2X7 receptors can also fashion the behavioral responses to painful stimuli and, in sharp contrast to the situation with P2X4 receptors, there is now a wealth of pharmacological antagonists to be used as experimental tools, some Liothyronine Sodium of which are in clinical trials (Gum et al., 2012; Jarvis, 2010). The predominant expression of P2X7 receptors in the nervous system is on microglia, astrocytes, and oligodendrocytes. However, some re-interpretation of experiments which used knock-out mice may be

required. The mice produced by Pfizer (Masin et al., 2012) continue to express two shortened, alternatively spliced, forms of the P2X7 receptor (P2X7 13B and P2X7 13C). The mice produced by Glaxo have a functional P2X7 splice variant (P2X7(k)) that continues to be expressed in these mice: the corresponding protein is widely expressed, but it has a different N-terminus and TM1 (Nicke et al., 2009). It forms receptors which are more sensitive to ATP and which undergo a more rapid increase in permeability to organic cations (a measure of pore dilation). The development of mechanical hypersensitivity in models of neuropathic pain is absent in the Glaxo P2X7 deletion mouse (Chessell et al., 2005), and a similar phenotype is observed in mice lacking both isoforms of IL-1β (Honore et al., 2006b). Mechanical hypersensitivity is also prevented by intrathecal P2X7 antagonist A-438079 (Kobayashi et al., 2011) and Brilliant Blue G (He et al., 2012) or systemic administration of P2X7 receptor antagonists (Honore et al., 2006a). These effects in pain models appear to require release of IL-1β, given that A-438079 blocks not only the ATP evoked release of IL-1β but also the release evoked by LPS (Clark et al., 2010).