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PERSPECTIVES IN PHARMACOLOGY

Painful Purinergic Receptors

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois

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, 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. 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, P2X_2/3, 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.

Address correspondence to: Dr. Michael F. Jarvis, Abbott Laboratories, R4PM, AP9A/311, 100 Abbott Park Road, Abbott Park, IL 60064. E-mail: michael.jarvis{at}abbott.com

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