RESUMO
AIMS: Bone cancer produces severe pain that is treated with opioids, but serious side effects limit opioid utilization. There is therefore a need to develop effective and safe non-opioid alternatives. The lipid mediator, Resolvin D1 (RvD1), could be a prospective candidate for cancer pain treatment. To assess RvD1 and other potential candidates, appropriate animal models that recapitulate clinical features must be used. Although several preclinical models of cancer pain have been developed, the influence of sex on the development of cancer pain and the effectiveness of RvD1 have not been studied. RESULTS: Using a mouse model of fibrosarcoma growth in and around the calcaneus bone, we demonstrated that the mechanical hyperalgesia in the tumor-bearing hind paw develops independently of sex, except that it developed a little sooner in female mice. A single intravenous injection of RvD1 (0.001-10 µg/kg) decreased hyperalgesia in both sexes with similar potency (ED50 = 0.0015 µg/kg) and efficacy. Repeated daily administration of 10 µg/kg RvD1 prolonged the analgesic effect and completely abolished hyperalgesia. This was also independent of sex. CONCLUSION: In this preclinical mouse model of bone cancer pain, the development of pain and the analgesic effectiveness of RvD1 are not influenced by sex.
Assuntos
Neoplasias Ósseas , Dor do Câncer , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos , Hiperalgesia , Animais , Feminino , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/secundário , Masculino , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/farmacologia , Camundongos , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Analgésicos/farmacologia , Analgésicos/administração & dosagem , Fibrossarcoma/tratamento farmacológico , Fibrossarcoma/patologia , Fibrossarcoma/complicações , Fatores Sexuais , Medição da DorRESUMO
ABSTRACT: Pain associated with bone cancer remains poorly managed, and chemotherapeutic drugs used to treat cancer usually increase pain. The discovery of dual-acting drugs that reduce cancer and produce analgesia is an optimal approach. The mechanisms underlying bone cancer pain involve interactions between cancer cells and nociceptive neurons. We demonstrated that fibrosarcoma cells express high levels of autotaxin (ATX), the enzyme synthetizing lysophosphatidic acid (LPA). Lysophosphatidic acid increased proliferation of fibrosarcoma cells in vitro. Lysophosphatidic acid is also a pain-signaling molecule, which activates LPA receptors (LPARs) located on nociceptive neurons and satellite cells in dorsal root ganglia. We therefore investigated the contribution of the ATX-LPA-LPAR signaling to pain in a mouse model of bone cancer pain in which fibrosarcoma cells are implanted into and around the calcaneus bone, resulting in tumor growth and hypersensitivity. LPA was elevated in serum of tumor-bearing mice, and blockade of ATX or LPAR reduced tumor-evoked hypersensitivity. Because cancer cell-secreted exosomes contribute to hypersensitivity and ATX is bound to exosomes, we determined the role of exosome-associated ATX-LPA-LPAR signaling in hypersensitivity produced by cancer exosomes. Intraplantar injection of cancer exosomes into naive mice produced hypersensitivity by sensitizing C-fiber nociceptors. Inhibition of ATX or blockade of LPAR attenuated cancer exosome-evoked hypersensitivity in an ATX-LPA-LPAR-dependent manner. Parallel in vitro studies revealed the involvement of ATX-LPA-LPAR signaling in direct sensitization of dorsal root ganglion neurons by cancer exosomes. Thus, our study identified a cancer exosome-mediated pathway, which may represent a therapeutic target for treating tumor growth and pain in patients with bone cancer.