A Systematic Review and Meta-Analysis of Anxiety- and Depressive-Like Behaviors in Rodent Models of Neuropathic Pain

Epidemiological studies have frequently shown the concurrence of chronic pain with symptoms of anxiety and depression, particularly in women. Animal models are useful to understand the complex mechanisms underlying comorbidities, but the wide range of methods employed and the wealth of evidence sometimes impedes effective translation and reproducibility. In this systematic review and meta-analysis, we aimed to synthesize the evidence regarding the influence of variables such as sex and species on anxiety- and depressive-like behaviors in rodent models of neuropathic pain. Following PROSPERO registration, we searched EMBASE, Scopus, and the Web of Science from their inception to November 24, 2023, identifying 126 studies that met the inclusion criteria. The Hedges’ g value for each experiment and study was calculated, and further subgroup and meta-regression analyses were performed. Neuropathic pain significantly reduced the time that rats and mice spent in the open arms of the elevated plus and zero mazes (g = −1.14), time spent in the center of the open field (g = −1.12), sucrose consumption in the sucrose preference test (g = −1.43), and grooming time in the splash test (g = −1.37) while increasing latency to feed in the novelty-suppressed feeding test (g = 1.59) and immobility in the forced swimming (g = 1.85) and tail suspension (g = 1.91) tests. Sex differences were observed, with weaker effects in female than in male rodents for several behavioral paradigms, and funnel plots identified positive publication bias in the literature. This meta-analysis emphasizes the effect of neuropathic pain on anxiety- and depressive-like behaviors in rodents, highlighting the importance of investigating sex differences in future experimental studies. In this systematic review and meta-analysis, we examined how neuropathic pain affects anxiety and depression-like behaviors in rodent models, focusing on the role of sex and species. We analyzed 126 experiments and found that neuropathic pain significantly increased anxiety- and depressive-like behaviors in rodents. Key findings included reduced time spent in anxiety-related environments and decreased interest in rewarding activities. Notably, sex differences emerged, with male rodents generally exhibiting stronger effects than female rodents. Positive publication bias was also identified. The study highlights the need to consider sex differences in future research on pain, anxiety, and depression using animal models.