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...

A decrease in pH occurs immediately after incision and is sustained for at least 4 days. During the period of decreased tissue pH, pain behaviors are evident. When the tissue pH returns to normal, pain behaviors are diminished. The decreased pH is localized at the incision site and not to areas surrounding the incision. Decreased pH likely contributes to nociceptor sensitization and pain related behaviors after incision. The magnitude of the pH change varies among tissues. An increase in hind paw skin temperature does not play a role in these pain-related behaviors.

Acutely, nerve growth factor (NGF) exerts profound effects on nociceptive transmission and produces pain and hyperalgesia. In the present study, we sought to determine the tissue levels and role of NGF after a plantar incision. A substantial increase in NGF protein expression occurred in skin 4-h, 1-day and 2-days and 5-days after incision comparing contralateral uninjured skin. Plantar incision did not change NGF levels in the tibial nerve and L4-L6 dorsal root ganglia. The therapeutic effect of a monoclonal antibody against endogenous NGF was evaluated by intraperitoneal administration of a single preoperative dose of anti-NGF. Of three different doses of anti-NGF used, the highest dose 2.8 mg/kg anti-NGF attenuated or almost abolished guarding pain scores at 4-h, 1-day (>80% decrease) and 2-days after incision. This effect is dose dependent in that lower doses (1, 0.1 mg/kg) were effective only at 1-day after incision. Anti-NGF also attenuated heat hyperalgesia at 1-day and 2-days after incision when the highest dose was used. However, treatment by anti-NGF did not affect C-fibers sensitized 1-day after incision in a glabrous skin-tibial nerve in vitro preparation. In conclusion, increased NGF was present in skin after plantar incision. NGF contributes to some incision-induced pain behaviors, guarding and heat hyperalgesia. Anti-NGF did not affect the extent of sensitization of C-fibers observed in vitro.

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