The analgesic effect of low dose focal irradiation in a mouse model of bone cancer is associated with spinal changes in neuro-mediators of nociception.
Despite the widespread use of radiotherapy to treat painful bone metastases, the mechanism underlying the analgesic effect of low dose ionizing radiation is unknown. Bone cancer pain is mostly associated with an inflammatory response dominated by local activation of osteoclasts and by astrogliosis in the spinal cord. We determined the effects of a 6 Gy irradiation given focally on osteolytic sarcoma cells inoculated in humeri of mice. Pain behavior was assessed using the rota-rod and the grip force test. Seven days post-irradiation (day 17 post-tumor implantation) the performance of mice markedly improved on the rotarod (non-irradiated, 67+/-16s vs irradiated, 223 +/- 22 s; P = 0.0005), and the grip force test (non-irradiated, 34 +/- 4 g vs irradiated, 55 +/- 2 g; P = 0.001). This improvement was similar to the analgesia achieved with 30 mg/kg of the cyclooxygenase (COX) inhibitor ketorolac (Rota-rod, 67 +/- 16 s vs 178 +/- 35 s; P = 0.01: grip force test, 34 +/- 4 g, vs 60 +/- 5 g; P = 0.003). Following irradiation, the tumor mass and the number of osteoclasts did not decrease while the expression of two pro-inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-alpha) increased. Tumor irradiation led to clear differences in the spinal cord. These include a decrease in glial activity (astrocytes and microglial cells) as well as pain mediators such as dynorphin, COX-2 and chemotactic cytokine receptor (CCR2). We conclude that the analgesic effect of low dose irradiation of bone cancer is associated with the alteration of nociceptive transmission in the central nervous system.
Vit
Jean-Philippe
JP
Department of Anatomy, University of California San Francisco, San Francisco, CA 94143-0452, USA Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA Departments of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA Departments of Neuroscience, Pharmacology and Dermatology, University of Minnesota, St. Paul, MN 55108, USA.
Ohara
Peter T
PT
Tien
Duc A
DA
Fike
John R
JR
Eikmeier
Laura
L
Beitz
Alvin
A
Wilcox
George L
GL
Jasmin
Luc
L
D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001522:Behavior, Animal / Q000187:drug effects / Q000528:radiation effects; D001859:Bone Neoplasms / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D004338:Drug Combinations; D005260:Female; D020910:Ketorolac / Q000008:administration & dosage; D051379:Mice; D008809:Mice, Inbred C3H; D009020:Morphine / Q000008:administration & dosage; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010146:Pain / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D013116:Spinal Cord / Q000378:metabolism* / Q000528:radiation effects; D016896:Treatment Outcome
D000701:Analgesics, Opioid; D000970:Antineoplastic Agents; D016207:Cytokines; D004338:Drug Combinations; D018377:Neurotransmitter Agents; D009020:Morphine; D020910:Ketorolac