A740003

Figure 13 A-317491 and A-740003, selective P2X3 and P2X7 ligand-gated ion channel antagonists, respectively.

primarily to sensory neurons, suggesting a role in pain transmission. The P2X3 messenger RNA (mRNA) occurs only in the trigeminal, dorsal root, and nodose ganglia, and the receptor is selectively expressed in sensory C-fiber neurons that project to the periphery and spinal cord, and which are predominantly nociceptors. In addition, P2X3 receptors located presynaptically at the central terminals of primary afferent neurons may have a facilitatory role to enhance neurotransmission, leading to a further increase in pain sensation.100

A role of ATP in pain transmission is consistent with the observed induction of pain by ATP upon application to human skin, and with reports that intradermal and intrathecal application of ATP and ATP analogs (e.g., a^-methylene ATP (a^metATP)) into the rat hind paw evokes acute nociceptive behavioral responses. Transgenic disruption of P2X3 receptors in rodents via knockout, antisense, or short interfering RNA (siRNA) manipulations leads to decreased nociceptive sensitivity.101'102 A-317491 (Figure 13), a potent and selective antagonist of homomeric P2X3 and heteromeric P2X2/3 receptors that when given systemically and intrathecally dose-dependently reduces nociception in animal models of inflammatory and neuropathic pain indicating that blockade of spinal P2X3 receptors may provide broad-spectrum analgesic effects in chronic pain states.100

P2Y2 receptors signal through protein kinase C (PKC) and, in turn, modulates the activation of TRPV1 receptors.103 Intrathecal antisense studies have also shown that P2X4 receptors acting via a spinal neural-microglial interaction alter nociceptive processing in neuropathic rodents.104 More recently, P2X7 receptor knockout mice have been characterized and show reduced inflammation and neuropathic pain as compared to wild-type mice.105 P2X7 receptors are not localized on small-diameter neurons in the periphery, but are found on gial cells in the dorsal root ganglion.106 Blockade of P2X7 receptors leads to inhibition of IL-1b release from macrophages and glial cells, while antagonists like A-740003 are active in pain models.110 In addition, P2X7 receptors mediate the ability of ATP to stimulate glutamate release from glial cells, thus providing an additional mechanism for ATP-mediated fast neurotransmission.107

6.14.7.8 Emerging Pain Targets

As indicated above, a developing concept in pain research is the appreciation that neuroimmune interactions participate in nociceptive signaling in chronic pain states.25 This has greatly added to the potential list of candidate mechanisms that may offer an avenue for analgesic intervention. In addition to traditional mechanisms associated with neuron-neuron communication, cytokines, chemokines, and inflammatory acute phase proteins are now known to contribute to nociceptive signaling. This collection of potential analgesic mechanisms is further complemented by findings that extracellular acid may also play a neuromodulatory role in the transmission of pain signals. Members of the TRP channel family are sensitive to both endogenous lipids as well as acidic pH. The activation of specific acid-sensing ion channels (ASICs) also contributes to the encoding of noxious stimulation.108 The development of selective antagonists of ASIC3 antagonist A-317567 (Figure 14) provided the demonstration that this acid-sensing channel contributes to both inflammatory hyperalgesia and pain associated with skin incision.108

As noted above, neurotrophic factors play important roles in the remodeling of the peripheral and central nervous systems in response to pain. Specifically, nerve growth factor (NGF) is a neurotrophin that is an important survival factor for sensory neurons.109 However, NGF also has pronociceptive actions, producing pain and enhancing hyperalgesia in both experimental animals and in human clinical studies. The recent development of small-molecule antagonists like ALE0540 and PD90780 (Figure 15) as well as anti-NGF antibodies has enabled studies demonstrating that these agents effectively reduce chronic arthritic pain, skin incision pain, and tactile allodynia following peripheral

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