The classification of receptors for adenosine, ATP and ADP (collectively called purinoceptors) has seen a number of developments in the past three years. The important division of receptors into two major classes 1 (1) adenosine (P 1 ) receptors and (2) P 2 purinoceptors, first suggested by Burnstock in 1978 (Ref.2), has been an abiding one that has set the stage for further subdivision of P 2 purinoceptors into P 2X and P 2Y subtypes on the basis of pharmacological properties 3 . Later, Dubyak 4 summarized the evidence that ATP worked through two different transduction mechanisms: intrinsic ion channels and G protein-coupled receptors. This information, coupled with the cloning of purinoceptors in 1993/94, led Abbracchio and Burnstock 5 to propose that purinoceptors should be classified in two families: G protein-coupled receptors termed P2Y purinoceptors, and intrinsic ion channels termed P2X purinoceptors. Developments in recent years have borne out these expectations and a revised nomenclature, essentially adopting the Abbracchio and Burnstock proposal, can now be proposed.

Note Added in Proof: Glaxo has recently reported 170 on GR 79236, an orally active A 1 -receptor selective agonist targeted for the treatment of type II diabetes. The Pzy receptor has been expressed from guinea pig brain mRNA.

P2X3 and P2X2/3 receptors are highly localized on peripheral and central processes of sensory afferent nerves, and activation of these channels contributes to the pronociceptive effects of ATP. A-317491 is a novel non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki ‫؍‬ 22-92 nM) and was highly selective (IC50 >10 M) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dosedependently (ED50 ‫؍‬ 30 mol͞kg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 ‫؍‬ 10 -15 mol͞kg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED 50 >100 mol͞kg s.c.) in reducing nociception in animal models of acute pain, postoperative pain, and visceral pain. The present data indicate that a potent and selective antagonist of P2X 3 and P2X2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X 3 and P2X2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.T he cloning and characterization of the P2X 3 receptor, a specific ATP-sensitive ligand-gated ion channel that is selectively localized on peripheral and central processes of sensory afferent neurons (1-3), has generated much interest in the role of this receptor in nociceptive signaling (4). The discovery of the P2X 3 receptor has provided a putative mechanism for previous reports that ATP, released from sensory nerves (5), produces fast excitatory potentials in dorsal root ganglion (DRG) neurons (6). These actions appear to be physiologically relevant because iontophoretic application of ATP to human skin elicits pain (7) and exogenously applied ATP enhances pain sensations in a human blister base model (8).The P2X 3 receptor is natively expressed as a functional homomer and as a heteromultimeric combination with the P2X 2 (P2X 2/3 ) receptor (1, 2, 9). Both P2X 3 -containing channels are expressed on a high proportion of isolectin IB4-positive neurons in DRG (3, 10). These receptors share similar pharmacological profiles (11), but differ in their acute desensitization kinetics (10, 12). Immunohistochemical studies have shown that P2X 3 receptor expression is up-regulated in DRG neurons and ipsilateral spinal cord after chronic constriction injury (CCI) of the sciatic nerve (13). Additionally, CCI results in a specific ectopic sensitivity to ATP that is not observed on contralateral (uninjured) nerves (14).Recently, the phenotyp...

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