Chronic Neuropathic Pain Affects Individual Emotional and Behavioral Disorders, Minocycline Shows Antidepressant Effect in Mouse Models

Background

Chronic Neuropathic Pain (CNP) has a profound impact on patients’ quality of life, but there are significant differences in individual responses to this pain. Some patients exhibit severe pain-related emotional and behavioral disorders, while others are relatively mild. The reasons for these differences are not yet clear, and there is great interest in revealing the mechanisms behind these differences. Studies have been conducted on the effects of psychosocial factors such as coping styles, pain catastrophizing, and self-efficacy on self-reported pain intensity in chronic pain patients (Arnstein et al. 1999; Pincus et al. 2002; Wood et al. 2016; Lazaridou et al. 2022). In addition, depression and anxiety are common disabling comorbidities, affecting approximately one-third to two-thirds of chronic pain patients (Cherif et al. 2020; Kec et al. 2022; Damci et al. 2022).

This research was conducted by a team led by Paul J. Austin from The University of Sydney, Australia. The article is titled “Minocycline abrogates individual differences in nerve injury-evoked affective disturbances in male rats and prevents associated supraspinal neuroinflammation,” published in Journal of Neuroimmune Pharmacology 2024, Volume 19, Page 30, DOI: https://doi.org/10.1007/s11481-024-10132-y.

Research Objectives and Sources

Main Authors and Institutions: The authors include Jayden A. O’Brien and Paul J. Austin, affiliated with the School of Medicine and Health and the Brain and Mind Centre at the University of Sydney. The study was published in the Journal of Neuroimmune Pharmacology in 2024.

Research Background: Chronic neuropathic pain triggers a range of complex emotional and behavioral disorders with significant individual differences. Although previous studies have revealed the alleviating effects of minocycline on emotional disorders in human and animal models, these studies generally did not explore how minocycline regulates individual emotional responses to nerve injury. Moreover, traditional behavioral paradigms have failed to capture the complexity of rodent behavior. Therefore, this paper explores the measurement of multiple spontaneous behavioral endpoints in male rats with nerve injury through a longitudinal natural foraging paradigm, studying the effects of long-term oral administration of minocycline on these changes.

Research Methods

Experimental Design: The experiment used 74 male Sprague-Dawley rats aged 6 weeks. Rats were housed individually in open-top cages with a 12:12 reverse light-dark cycle. The experimental design included chronic constriction injury (CCI) and minocycline treatment, motor and sensory tests, and emotional and spatial memory behavioral tests.

Specific Procedures: 1. CCI Surgery and Minocycline Administration: Rats were divided into CCI model and sham surgery groups, with some CCI and sham surgery rats receiving oral minocycline (40 mg/kg/day) administration. 2. Quantitative Motor and Sensory Tests: Rotarod and dynamic plantar aesthesiometer were used to determine the rats’ motor coordination and mechanical allodynia. 3. Emotional and Spatial Memory Behavioral Tests: A modified radial arm maze paradigm was used to analyze rats’ foraging behavior and emotional behavior through video recording and coding. 4. Tissue Processing and Immunofluorescence Staining: On day 21 post-surgery, immunofluorescence staining was performed on rat brains, with quantitative analysis of neuronal and glial cell marker expression.

Research Results

Behavioral Test Results: 1. Emotional Behavior Assessment: Among 36 vehicle-treated CCI rats, 8 showed emotional disturbances in the first week post-surgery (about 22% of the total), which decreased in weeks 2 and 3. Minocycline treatment completely prevented the occurrence of emotional disturbances while only partially alleviating mechanical allodynia. CCI rats spent significantly more time in the center area in weeks 1-3 post-surgery compared to minocycline-treated and sham surgery groups, while minocycline-treated rats showed no significant differences at any time point. 2. Mechanical Allodynia: Minocycline partially alleviated mechanical pain in CCI rats but did not significantly alter the differences in mechanical pain between subgroups affecting emotional responses.

Glial and Neuronal Activation: 1. Fosb Expression: Significantly increased in neurons of bilateral ventral hippocampal CA1 and CA3 regions in CCI rats, while showing significant reduction in the minocycline-treated group. 2. Microglial Morphology Changes: Persistent changes in microglial morphology were observed in specific prefrontal cortex subregions of CCI model rats, showing a low-level activation state, while the minocycline-treated group showed no significant differences.

Discussion and Conclusion

Minocycline significantly reduced emotional disturbances in the subgroup of CCI rats with disturbed foraging behavior by regulating the multifunctional effects of microglia, and decreased related upstream neuronal activation. Furthermore, future research should explore its effects on fibroblasts, cytokine signaling pathways, and interactions.

Research Value: This paper provides new insights into the potential mechanisms of minocycline in alleviating neuropathic pain-related emotional disorders and emphasizes the key role of upstream glial and neuronal regulation in emotional responses. This helps us design more effective treatment strategies in the future to improve the quality of life for patients with chronic neuropathic pain.