title: Evoked pain behavior and spinal glia activation is dependent on tumor necrosis factor receptor 1 and 2 in a mouse model of bone cancer pain.
abstract: Bone-cancer-related pain is one of the most disabling factors in patients suffering from primary bone cancer or bone metastases. Recent studies point toward an important role of proinflammatory cytokines, example tumor necrosis factor-alpha (TNF), for tumor growth and bone-cancer-associated pain. Mechanisms by which TNF, through its receptor subtypes, TNF receptor 1 (TNFR1) and -2 (TNFR2), elicits altered sensation and pain behavior, are still incompletely understood. To look for a potential role of TNF in bone cancer pain, cancer-related pain was analyzed in fibrosarcoma-bearing C57Bl/6J wild type mice after systemic antagonism of TNF. To further clarify the role of TNF receptor (TNFR) in bone-cancer pain, naive and fibrosarcoma-bearing C57Bl/ 6J wild type and transgenic mice with a deficiency of TNFR1 (TNFR1ko), TNFR2 (TNFR2ko), and TNFR1+2 (TNFR1+2ko) were compared regarding cancer-related pain and hyperalgesia, tumor growth, osteoclast activation, and spinal astrogliosis. Systemic antagonism of TNF significantly alleviated tactile hypersensitivity and spontaneous bone-cancer-related pain behavior. Most interestingly, combined deletion of the TNFR1 and TNFR2, but not of either gene alone, almost completely inhibited the development of tactile hypersensitivity, whereas spontaneous pain behavior was transiently increased. Accordingly, spinal astrogliosis was markedly reduced, whereas tumor growth was significantly increased in TNFR1+2ko mice. In contrast, deletion of the TNFR1 or TNFR2 gene alone did not change tumor growth or spinal astrogliosis. Our findings suggest that the combined absence of TNFR1 and TNFR2 is necessary for the attenuation of cancer-related tactile hypersensitivity and concomitant spinal astrogliosis, whereas tumor growth seems to be inhibited by combined TNFR activation. These findings support the hypothesis of cytokine-dependent pain development in cancer pain. Differential targeting of TNFR activation could be an interesting strategy in bone-cancer-related pain conditions.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Geis
authors.forename: M
authors.initials: M
authors.lastname: Graulich
authors.forename: A
authors.initials: A
authors.lastname: Wissmann
authors.forename: T
authors.initials: T
authors.lastname: Hagenacker
authors.forename: J
authors.initials: J
authors.lastname: Thomale
authors.forename: C
authors.initials: C
authors.lastname: Sommer
authors.forename: M
authors.initials: M
authors.lastname: Schäfers
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology; D001522:Behavior, Animal; D001859:Bone Neoplasms / Q000503:physiopathology / Q000556:secondary*; D000068800:Etanercept; D005354:Fibrosarcoma / Q000503:physiopathology / Q000556:secondary*; D005911:Gliosis / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D006930:Hyperalgesia / Q000503:physiopathology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007794:Lameness, Animal / Q000209:etiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000502:physiology*; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010146:Pain / Q000209:etiology / Q000503:physiopathology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology*; D014110:Touch; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D007074:Immunoglobulin G; D009363:Neoplasm Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C469948:Tnfrh2 protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept