Evaluate the current evidence of using ethologically relevant pain-related behaviours in rodent persistent pain research and determine how they are influenced by experimental confounding factors
File(s)
Author(s)
Zhang, Xue Ying
Type
Thesis
Abstract
Developing effective analgesics for chronic pain is crucial due to the limitations of current drugs, yet many promising candidates fail in clinical translation. Researchers are exploring complex ethologically relevant behaviours as non-evoked, persistent pain-related outcome measures to enhance translational success. However, their reliability across different disease models is unclear and they can be influenced by factors beyond pain. For this PhD, three systematic reviews and meta-analyses were conducted to evaluate the utility of burrowing, thigmotaxis, and rat grimace scale (RGS) score as pain-related outcome measures.
Systematic searches on multiple databases yielded retrieved studies, which were then screened against the pre-defined eligibility criteria. Included studies had their study design characteristics and experimental data extracted according to the pre-defined protocol. Effect sizes were calculated via random-effects meta-analysis. Additional analyses assessed sources of heterogeneity, risk of bias, publication bias, and correlations between ethological behaviours and stimulus-evoked limb withdrawal response.
The meta-analyses suggested that burrowing, thigmotaxis, and RGS score serve as adequate outcome measures for persistent pain, showing negative impacts from injuries and disease models associated with persistent pain, which were attenuated by analgesic drug treatments. However, their full validity requires confirmation with more data. Recommendations were made regarding specific drugs as positive controls in certain rodent disease models. Sources of heterogeneity were inconclusive due to limited data availability. Considerations included the use of sex-balanced animals and genetically diverse strains. Poor reporting of methodological quality measures hindered internal validity assessment, resulting in unclear risk of bias for most studies. Positive correlations were found between stimulus-evoked limb withdrawal and both burrowing and thigmotaxis. Limitations were also discussed.
The empirical evidence acquired aids in refining study designs, elevating experimental methodological quality, promoting reporting transparency in preclinical studies, and advancing the application of the 3Rs (Replacement, Reduction, Refinement) principle in animal pain research.
Systematic searches on multiple databases yielded retrieved studies, which were then screened against the pre-defined eligibility criteria. Included studies had their study design characteristics and experimental data extracted according to the pre-defined protocol. Effect sizes were calculated via random-effects meta-analysis. Additional analyses assessed sources of heterogeneity, risk of bias, publication bias, and correlations between ethological behaviours and stimulus-evoked limb withdrawal response.
The meta-analyses suggested that burrowing, thigmotaxis, and RGS score serve as adequate outcome measures for persistent pain, showing negative impacts from injuries and disease models associated with persistent pain, which were attenuated by analgesic drug treatments. However, their full validity requires confirmation with more data. Recommendations were made regarding specific drugs as positive controls in certain rodent disease models. Sources of heterogeneity were inconclusive due to limited data availability. Considerations included the use of sex-balanced animals and genetically diverse strains. Poor reporting of methodological quality measures hindered internal validity assessment, resulting in unclear risk of bias for most studies. Positive correlations were found between stimulus-evoked limb withdrawal and both burrowing and thigmotaxis. Limitations were also discussed.
The empirical evidence acquired aids in refining study designs, elevating experimental methodological quality, promoting reporting transparency in preclinical studies, and advancing the application of the 3Rs (Replacement, Reduction, Refinement) principle in animal pain research.
Version
Open Access
Date Issued
2024-04-25
Date Awarded
2026-02-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Rice, Andrew SC
Soliman, Nadia
Sponsor
Medical Research Council (Great Britain)
Grant Number
MR/N014103/1
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)