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 subtypes, including P2X3, P2X2/3, 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. Furthermore, activation of P2Y2 receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X3, P2X2/3, and P2Y receptors) or indirectly through neural-glial 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.
Footnotes
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D.D.-R., S.M., C.-C.S., P.H., and M.F.J. contributed equally to this perspective.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.105890.
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ABBREVIATIONS: ADO, adenosine; α,β-meATP, α,β-methyleneATP; IL-1, interleukin-1; DRG, dorsal root ganglion; TRPV1, transient receptor potential-1; PPADs, pyridoxal phosphate-6-azophenyl-2-4-disulfonic acid; A-317334, S-enantiomer of A-317491.
- Received August 16, 2007.
- Accepted November 21, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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