Page 30 - JCBP-2-1

Journal of Clinical and
Basic Psychosomatics The endocannabinoid system

in a heightened heart rate. The intricate interplay between elevated cortisol levels due to chronic stress. The intricate
molecular involving MR and GR activation, influencing relationship between cortisol, GRs, and gut function
vascular and cardiac tissues, respectively, provides a extends beyond motility regulation and can contribute
mechanistic understanding of how dysregulated cortisol to alterations in the composition of the gut microbiota.
levels contribute to the cardiovascular manifestations that This, in turn, may give rise to increased gas production
are characteristic of PSD [65-67] . and abdominal distension, both contributing factors to the
Moreover, cortisol’s influence on the autonomic sensation of bloating [73,74] .
nervous system also affects heart rate and cardiac output, Furthermore, the activation of GRs within the
causing individuals with PSD to experience palpitations gastrointestinal tract is intricately linked to the gut-
and a racing heart, which can be both alarming and brain axis. Dysregulated cortisol levels disrupt the
distressing. This heightened sympathetic nervous system communication between the gut and the central nervous
activity, characterized by increased heart rate, is further system. This disruption has the potential to amplify the
intensified by stress and emotional distress . perception of visceral pain, intensifying the patient’s
[68]
On the other hand, cortisol also significantly impacts discomfort and complicating their clinical presentation
the gastrointestinal system. The gastrointestinal tract within the context of PSD [72,75-79] .
hosts an abundance of GRs, and their activation by 2.4. Altered sensitivity to pain and discomfort
cortisol modulates neuronal signaling within the gut. This
modulation, in turn, influences visceral sensitivity and Cortisol significantly influences pain perception and
has the potential to amplify the perception of pain. On sensitivity, contributing to the complex symptomatology
activation by cortisol, GR can exert regulatory control over of PSD. The modulation of pain perception by cortisol is
the expression of genes associated with the production and mediated through its interaction with both central and
[80]
release of neurotransmitters involved in pain perception, peripheral corticosteroid receptors .
such as substance P and serotonin. Consequently, changes The impact of cortisol on pain perception involves
in the levels of these neurotransmitters can impact its action on nociceptors, specialized sensory receptors
neuronal signaling and sensitivity in the gastrointestinal responsible for detecting painful stimuli (Figure 1C). This
tract. In addition, alterations in gene expression driven interaction may result in enhanced pain transmission or the
by GR activation may lead to neuronal sensitization, a amplification of pain signals. Notably, in individuals with
phenomenon wherein gut neurons become more responsive PSD, this heightened sensitivity to pain and discomfort is a
to stimuli. This heightened sensitivity can intensify characteristic feature .
[81]
the perception of pain signals, thereby contributing to
increased visceral sensitivity (Figure 1C) . The intricate molecular mechanism through which
[69]
cortisol influences pain perception, particularly by acting
In addition, GR activation modulates the expression on nociceptors – specialized sensory receptors responsible
of genes associated with the production of inflammatory for detecting painful stimuli – involves a cascade of
mediators. For example, GR activation leads to the events at the cellular and molecular levels. On binding
inhibition of proinflammatory genes by preventing the to GRs on the membrane of nociceptor cells, cortisol
binding of other transcription factors, such as NF-κB, a initiates a series of intracellular processes. The activated
key regulator of inflammatory gene expression, to their GRs translocate into the nucleus, where they function as
respective promoter regions. Simultaneously, GR activation transcription factors, modulating the expression of genes
promotes the transcription of anti-inflammatory genes, crucial for nociceptor function and pain perception. This
such as glucocorticoid-induced leucine zipper (GILZ) and regulatory process includes the regulation of ion channels
annexin-1. These genes play pivotal roles in the resolution pivotal for nociceptor excitability, such as voltage-gated
of inflammation. Chronic inflammation within the gut sodium channels, essential for action potential generation
may further sensitize neurons and contribute to heightened and propagation. In addition, cortisol, through GR
pain perception [69,72] . activation, can influence the expression of genes related to
Moreover, the activation of GRs exerts regulatory neurotransmitter release from nociceptor terminals. This
effects on intestinal motility. Cortisol’s interaction with modulation encompasses the regulation of neuropeptides,
these receptors has the potential to influence the smooth such as substance P, and neurotransmitters, such as
muscle activity of the intestines, consequently impacting glutamate and gamma-aminobutyric acid (GABA),
the pace of contractions. This modulation of intestinal all of which play pivotal roles in nociceptive signaling
motility may manifest in symptoms such as diarrhea, (Figure 1D). Furthermore, cortisol’s impact extends to
which is commonly reported in individuals experiencing the modulation of inflammatory mediators, including

Volume 2 Issue 1 (2024) 6 https://doi.org/10.36922/jcbp.2288