Received for publication August 16, 2007.
Revised November 21, 2007.
Accepted for publication November 21, 2007.

Painful Purinergic Receptors

Abstract

Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies including genetic disruption studies and the development of selective antagonists has indicated that the activation of P2X receptor subytpes, including P2X₃, P2X_2/3, P2X₄ and P2X₇, and P2Y (e.g. P2Y₂) receptors can modulate pain. For example, administration of a selective P2X₃ antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X₄ receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X₇ receptor also reduce sensitization in animal models of inflammatory and neuropathic pain providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Additionally, activation of P2Y₂ receptors leads to sensitization of polymodal TRPV1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g. P2X₃, P2X_2/3 and P2Y receptors) or indirectly through neural-gial cell interactions (P2X₄ and P2X₇ receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity.

Key words: ATP, allodynia, hyperalgesia, pain, purinergic receptors, purines

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