a-839977 and Pain

ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including peripheral macrophages and glial cells in the CNS. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta and following prolonged agonist exposure, the formation of cytolytic pores in plasma membranes. Both the localization and functional consequences of P2X(7) receptor activation indicate a role in inflammatory processes. The phenotype of P2X(7) receptor gene-disrupted mice also indicates that P2X(7) receptor activation contributes to ongoing inflammation. More recently, P2X(7) receptor knockout data has also suggested a specific role in inflammatory and neuropathic pain states. The recent discovery of potent and highly selective antagonists for P2X(7) receptors has helped to further clarify P2X receptor pharmacology, expanded understanding of P2X(7) receptor signaling, and offers new evidence that P2X(7) receptors play a specific role in nociceptive signaling in chronic pain states. In this review, we incorporate the recent discoveries of novel P2X(7) receptor-selective antagonists with a brief update on P2X(7) receptor pharmacology and its therapeutic potential.

Topics: Adenosine Triphosphate; Animals; Chronic Disease; Humans; Inflammation; Pain; Purinergic P2 Receptor Agonists; Purinergic P2 Receptor Antagonists; Rats; Receptors, Purinergic P2; Receptors, Purinergic P2X7; Signal Transduction

Pain is a common and debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of molecular events, including mechanisms observed in inflammatory and neuropathic pain states, but also changes unique for cancer-induced bone pain. The P2X7 receptor (P2X7R) is involved in a variety of cellular functions and has been linked to both inflammatory and neuropathic pain. Here we study the analgesic potential of P2X7R antagonism in a rat model of cancer-induced bone pain. In cancer-bearing animals, the P2X7R antagonist A839977 attenuated dorsal horn neuronal responses in a modality and intensity-specific way. Spinal application of 0.4-mg/kg and 1.2-mg/kg A839977 significantly reduced the evoked responses to high-intensity mechanical and thermal stimulation, whereas no effect was seen in response to low-intensity or electrical stimulation. In contrast, A839977 had no effect on the tested parameters in naïve or sham animals. In awake animals, 40-mg/kg A839977 (i.p.) significantly reduced both early- and late-stage pain behavior. In contrast, no effect was observed in sham or vehicle-treated animals. The results suggest that the P2X7R is involved in the mechanisms of cancer-induced bone pain, and that P2X7R antagonism might be a useful analgesic target. No effect was observed in sham or naïve animals, indicating that the P2X7R-mediated effect is state-dependent, and might therefore be an advantageous target compared to traditional analgesics.

Topics: Analgesics, Non-Narcotic; Animals; Bone Neoplasms; Carcinoma, Ductal, Breast; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mammary Neoplasms, Animal; Motor Activity; Neoplasm Transplantation; Pain; Posterior Horn Cells; Purinergic P2X Receptor Antagonists; Pyridines; Rats, Sprague-Dawley; Receptors, Purinergic P2X7; Tetrazoles

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) has been implicated in both inflammatory processes and nociceptive neurotransmission. Activation of P2X7 receptors is the mechanism by which ATP stimulates the rapid maturation and release of IL-1beta from macrophages and microglial cells. Recently, selective P2X7 receptor antagonists have been shown to reduce inflammatory and neuropathic pain in animal models. However, the mechanisms underlying these analgesic effects are unknown. The present studies characterize the pharmacology and antinociceptive effects of a structurally novel P2X7 antagonist. A-839977 potently (IC50=20-150 nM) blocked BzATP-evoked calcium influx at recombinant human, rat and mouse P2X7 receptors. A-839977 also potently blocked agonist-evoked YO-PRO uptake and IL-1beta release from differentiated human THP-1 cells. Systemic administration of A-839977 dose-dependently reduced thermal hyperalgesia produced by intraplantar administration of complete Freund's adjuvant (CFA) (ED50=100 micromol/kg, i.p.) in rats. A-839977 also produced robust antihyperalgesia in the CFA model of inflammatory pain in wild-type mice (ED50=40 micromol/kg, i.p.), but the antihyperalgesic effects of A-839977 were completely absent in IL-1alphabeta knockout mice. These data demonstrate that selective blockade of P2X7 receptors in vivo produces significant antinociception in animal models of inflammatory pain and suggest that the antihyperalgesic effects of P2X7 receptor blockade in an inflammatory pain model in mice are mediated by blocking the release of IL-1beta.

Topics: Adenosine Triphosphate; Analgesics, Non-Narcotic; Animals; Calcium; Cell Line; Dose-Response Relationship, Drug; Freund's Adjuvant; Hot Temperature; Humans; Interleukin-1alpha; Interleukin-1beta; Male; Mice; Mice, Inbred BALB C; Mice, Knockout; Pain; Purinergic P2 Receptor Antagonists; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P2; Receptors, Purinergic P2X7; Recombinant Proteins; Tetrazoles