The glutamatergic system and pain: influence of stress, oestrous cycle and gut microbiota

Women have a higher incidence of various visceral and neuropathic chronic pain conditions. Most of the animal studies investigating pain mechanisms show oestrogen to be pronociceptive. However, similar studies in healthy humans are equivocal. The predisposition of chronic pain conditions in female patients with a history of stress emphasises the role of chronic stress in the pathogenesis of these conditions. Since glutamatergic system plays an import role in the transmission of pain-related information in the central nervous system (CNS), its impaired modulation may be a key phenomenon responsible for the pathogenesis of pain conditions and associated gender differences. The microbiota-gut-brain axis is shown to be capable of influencing the CNS function in health and various diseases, but as yet it is to be determined whether it has any role in the modulation of pain-related central nervous mechanisms. Extensive research is being carried out to understand the mechanisms through which sex hormones and chronic stress may influence the pain neurotransmission resulting in sex differences in pain. However, these mechanisms are not fully understood yet. As microbiota-gut-brain axis has been shown to influence a number of CNS disorders, and there is emerging evidence of its role in pain modulation in preclinical studies, we specifically concentrated on gut microbiota and its associated mechanisms influencing pain sensitivity. Our objectives were to explore the interplay between sex, stress, glutamatergic system, gut microbiota, and their effect on pain responses. We performed experiments both in animals and healthy humans. We were able to demonstrate that in rats, synaptic glutamate metabolism in the spinal cord and anterior cingulate cortex of brain varied significantly depending upon the phase of the oestrous cycle. Endogenous oestrogen exerted its effects through oestrogen receptor-α and was also shown to regulate glutamate receptor subunits expression. By utilising animal models of visceral hypersensitivity and stress (early-life stress & depression) in Wistar-Kyoto (WKY) and maternally separated rats, we could demonstrate that stress significantly altered pain responses through modifying the glutamatergic system and such effect was oestrous phase specific. In WKY rats, short-chain fatty acid producing gut microbiota abundance had a positive correlation with synaptic glutamate transporter function in a sex-specific manner. Finally, in healthy humans, we demonstrated a positive correlation between the abundance of butyrate producing bacteria in the bowel and pain sensitivity. Furthermore, hormonal contraceptive use was associated with increased lipopolysaccharide-binding protein levels. Taken together, our results show that oestrogen plays a vital role in glutamatergic neurotransmission and pain responses. Aberrant changes in the pain-related sensory mechanisms may develop by factors such as stress and altered gut microbiota. The emerging relationship between sex hormones, neuroendocrine system, and the gut microbiota in relation to pain modulation supports further investigations in large scale studies. Trials are needed to establish if interventions to correct gut microbiota imbalance can have analgesic effects