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Sex differences and oxytocinergic transmission impact on chronic pain in animal models and humans

Abstract

Chronic pain conditions have a significantly higher prevalence in women and involve physical, psychological, and sociocultural aspects. However, only 20% of neuroscience preclinical studies are performed in males and females. Previous findings described that social isolation is capable of interfering with pain responses. From a neurobiological viewpoint, the neuromodulator oxytocin is associated with the regulation of pain and processes that involve social behaviors. In addition, previous studies indicated sex differences in the oxytocin action within brain areas that modulate emotional and pain responses. From a clinical standpoint, chronic pain can be triggered by surgical procedures, and these conditions reach 50% of individuals undergoing different types of surgeries. In this perspective, there is a shortage of data about biological sex and oxytocin neurotransmission affect the sensitive and emotional components of pain in this condition. The objectives outlined for this study are aimed at two approaches: Pre-clinical, to be performed in mice: (i) to evaluate the influence of sex on nociceptive, anxiety, and depression responses and their correlation with oxytocin plasma levels in the animals subjected to hyperalgesic priming model; (ii) to verify whether oxytocin treatment alters responses related to pain, anxiety, and depression and if the effects differ in males and females and neurofunctional alterations on the spinal cord, dorsal root ganglion, RVM, periaqueductal gray matter, amygdala, insula, and anterior cingulate cortex (iii) to investigate the oxytocinergic projections to pain modulation-related areas in the limbic system (eg, paraventricular nucleus (PVN)-the amygdala, insula, cortex, RVM and periaqueductal gray matter), (iv) to stimulate chemogenetically the oxytocin neurons through the use of genetically modified animals (Oxytocin-cre mice), aiming to verify effects on nociceptive and emotional responses in males and females under hyperalgesic primming model; Clinical, evaluate possible sex differences in oxytocinergic neurotransmission in tissue collected postmortem from men and women affected by chronic pain; (i) BDNF expression and characterization of oxytocinergic receptors in spinal cord, dorsal ganglia, and brain and midbrain regions in frozen tissue; (ii) Functional responses in cultured neurons to oxytocin in fresh spinal cord tissue and ganglia. In summary, the main axis of the proposal is to investigate the biopsychosocial impact on the sensitive and affective-emotional components in post-surgical chronic pain, and how oxytocin modulates these responses. With the obtention of these findings and the identification of the biological and emotional influence in the management of chronic pain, this study seeks to provide practical tools aimed to improve the clinical management of chronic pain. (AU)

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