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Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect with ineffective preventative and curative treatment. Currently, only Duloxetine has been recommended as effective treatment for CIPN, which has shown individual-dependent, short-term analgesic effects, with limiting adverse effects and poor bioavailability. The neuropeptide, oxytocin, may offer significant analgesic and anxiolytic potential, as it exerts central and peripheral attenuating effects on nociception. However, it is unknown whether the intervention administered in a model of CIPN is an effective therapeutic alternative or adjuvant. Materials and Methods The intervention was divided into two phases. Phase 1 aimed to induce CIPN in adult Wistar rats using the chemotherapeutic agent Paclitaxel. Mechanical (electronic von Frey filament) and thermal (acetone evaporation test and Hargreaves test) hypersensitivity testing were used to evaluate changes due to the neuropathic induction. Phase 2 consisted of a 14-day intervention period with saline (o.g.), duloextine (o.g.), or oxytocin (i.n.) administered as treatment. Following the intervention, anxiety-like behaviour was assessed using the elevated plus maze (EPM) and light-dark box protocols. Analysis of peripheral plasma corticosterone, peripheral plasma oxytocin, and hypothalamic oxytocin concentrations were assessed using ELISA assays. Results The findings showed that we were able to successfully establish a model of chemotherapy-induced peripheral neuropathy during Phase 1, determined by the increase in mechanical and thermal nociceptive responses following Paclitaxel administration. Furthermore, the animals treated with oxytocin displayed a significant improvement in mechanical sensitivity over the intervention phase, indicative of an improvement in nociceptive sensitivity in the presence of neuropathic pain. Animals that received Paclitaxel and treated with oxytocin also displayed significantly greater explorative behaviour during the EPM, indicative of a reduced presence of anxiety-like behaviour. Conclusion Our results support the hypothesis that intranasally administered oxytocin may augment the analgesic and anxiolytic effects of duloxetine in a chemotherapy induced peripheral neuropathy model in a Wistar rat. Future studies should consider administering the treatments in combination to observe the potential synergistic effects.
RESUMO
Stress is a complex and multifaceted phenomenon that can significantly influence both aggressive behavior and sexual function. This review explores the intricate relationship between stress, neuromodulator pathways, and epigenetics, shedding light on the various mechanisms that underlie these connections. While the role of stress in both aggression and sexual behavior is well-documented, the mechanisms through which it exerts its effects are multifarious and not yet fully understood. The review begins by delving into the potential influence of stress on the Hypothalamic-Pituitary-Adrenal (HPA) axis, glucocorticoids, and the neuromodulators involved in the stress response. The intricate interplay between these systems, which encompasses the regulation of stress hormones, is central to understanding how stress may contribute to aggressive behavior and sexual function. Several neuromodulator pathways are implicated in both stress and behavior regulation. We explore the roles of norepinephrine, serotonin, oxytocin, and androgens in mediating the effects of stress on aggression and sexual function. It is important to distinguish between general sexual behavior, sexual motivation, and the distinct category of "sexual aggression" as separate constructs, each necessitating specific examination. Additionally, epigenetic mechanisms emerge as crucial factors that link stress to changes in gene expression patterns and, subsequently, to behavior. We then discuss how epigenetic modifications can occur in response to stress exposure, altering the regulation of genes associated with stress, aggression, and sexual function. While numerous studies support the association between epigenetic changes and stress-induced behavior, more research is necessary to establish definitive links. Throughout this exploration, it becomes increasingly clear that the relationship between stress, neuromodulator pathways, and epigenetics is intricate and multifaceted. The review emphasizes the need for further research, particularly in the context of human studies, to provide clinical significance and to validate the existing findings from animal models. By better understanding how stress influences aggressive behavior and sexual function through neuromodulator pathways and epigenetic modifications, this research aims to contribute to the development of innovative protocols of precision medicine and more effective strategies for managing the consequences of stress on human behavior. This may also pave way for further research into risk factors and underlying mechanisms that may associate stress with sexual aggression which finds application not only in neuroscience, but also law, ethics, and the humanities in general.