title: P2X7 receptor-mediated analgesia in cancer-induced bone pain.
abstract: 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.
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: falk@sund.ku.dk.
authors: S
authors: S
authors: Falk
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors: S D
authors: SD
authors: Schwab
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors: M
authors: M
authors: Frøsig-Jørgensen
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors: R P
authors: RP
authors: Clausen
authors: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
authors: A H
authors: AH
authors: Dickenson
authors: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Electronic address: amhe@sund.ku.dk.
authors: A-M
authors: AM
authors: Heegaard
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications / Q000503:physiopathology*; D018270:Carcinoma, Ductal, Breast / Q000503:physiopathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000503:physiopathology; D009043:Motor Activity / Q000187:drug effects; D009368:Neoplasm Transplantation; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D013777:Tetrazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C545178:A-839977; D018712:Analgesics, Non-Narcotic; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058486:Receptors, Purinergic P2X7; D013777:Tetrazoles
keywords: P2X7R antagonism; analgesia; cancer-induced bone pain; neuronal responses; pain behavior