Behavioral Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain-(-Related) Phenotypes in Rats with Bone Cancer

Author:

Segelcke Daniel1ORCID,Linnemann Jan1,Pradier Bruno12ORCID,Kronenberg Daniel3ORCID,Stange Richard3ORCID,Richter S. Helene4,Görlich Dennis5ORCID,Baldini Nicola67,Di Pompo Gemma7ORCID,Verri Waldiceu A.8ORCID,Avnet Sofia6ORCID,Pogatzki-Zahn Esther M.1

Affiliation:

1. Department of Anesthesiology Intensive Care and Pain Medicine, University Hospital Münster, 48149 Münster, Germany

2. Department of Clinical Radiology, Translational Research Imaging Center, University Hospital Münster, 48149 Münster, Germany

3. Institute for Musculoskeletal Medicine, University Hospital Münster, 48149 Münster, Germany

4. Department of Behavioural Biology, University of Münster, 48149 Münster, Germany

5. Institute of Biostatistics and Clinical Research, University of Münster, 48149 Münster, Germany

6. Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy

7. Biomedical Science and Technologies and Nanobiotechnologies Laboratory, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy

8. Centro de Ciências Biológicas, Departamento de Ciências Patológicas, Universidade Estadual de Londrina, Londrina 86057-970, Brazil

Abstract

Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. The use of rodent models is the most common approach to uncovering the mechanisms underlying CIBP; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative of relevant pain in patients. To improve the accuracy and strength of the preclinical, experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a home-cage monitoring assay (HCM). Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of the CIBP-phenotype, including evoked and non-evoked based assays and HCM. Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and differently) in males. Additionally, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex. This multimodal battery allows for an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalizability of results and provide information for targeted drug development in the future.

Funder

EU Grant

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Publisher

MDPI AG

Subject

Cancer Research,Oncology

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