Neuropathic pain results from injuries or diseases affecting the somatosensory system, impacting 7–10% of the global population. Additionally, psychological factors such as depression and anxiety are linked to heightened pain perception. Studies using animal models with chronic sciatic nerve constriction injury (CCI) are essential for investigating its pathophysiology. Although pharmacological treatment is widely used, environmental enrichment (EE) and voluntary exercise (VE) have shown efficacy as adjuvant interventions in managing neuropathic pain, including reducing anxiety- and depression-like behaviors associated with pain exacerbation. EE provides motor, sensory, social, and cognitive stimuli, which can be enhanced by VE, consisting of voluntary physical activity performed by the animal on a freely accessible running wheel. However, few studies have compared the effects of EE alone versus EE combined with VE.

To compare the effects of EE with or without VE on anxiety- and depression-like behavior in a neuropathic pain model induced by CCI.

Twenty female BALB-C mice aged 7–8 weeks, weighing 30–35 g, were obtained from the Instituto Evandro Chagas (IEC) animal facility after approval by the animal research ethics committee. The animals were divided into four groups: CCI, CCI + VE, CONTROL, and CONTROL + VE. All groups received EE; the CCI groups underwent nerve constriction surgery, while control groups were not exposed to surgical intervention. Anxiety- and depression-like behaviors were assessed using the Open Field (OF) test, where animals were placed in a 30 × 30 × 40 cm apparatus for 5 minutes and filmed for later analysis. Statistical analyses included the Shapiro-Wilk normality test and one-way ANOVA with Tukey’s post-hoc test, using Prism 9 software. p-values < 0.05 were considered significant.

In the OF test, the CCI + VE group maintained total distance traveled like pre-injury measurements, with no significant changes over the 28-day experiment. In contrast, the CCI group showed increased immobility and progressive distance reduction on days 14, 21, and 28 (one-way ANOVA, F (4,16) = 6.47; p = 0.003). Furthermore, time spent in the corners of the apparatus increased significantly in the CCI group compared to pre-injury (one-way ANOVA, F (4,16) = 3.34; p = 0.03).

The combination of VE with EE enhanced the reduction of anxiety- and depression-like behaviors in mice subjected to CCI.

These findings suggest that combined non-pharmacological interventions could be promising strategies for managing neuropathic pain through reducing anxiety- and depression-like behaviors, warranting further studies to explore their mechanisms and clinical applications.