REVIEW OF KNOWLEDGE

1. STRESS-INDUCED VISCERAL PAIN
By
Muhammad Kabir, ADAMU
(U13HP1046)
TERM PAPER PRESENTATION
Supervisor: Dr. Isa Ahmed-Sherif
May, 2018
Wednesday, April 5, 2023 1

2. SYNOPSIS
• INTRODUCTION
• STRESS
• VISCERAL PAIN
• MECHANISM INVOLVED IN SRESS-INDUCED
VISCERAL PAIN
• NEUROTRANSMITTERS IN STRESS PATHWAY THAT
MODULATE VISCERAL PAIN
• ANIMAL MODELS
• TREATMENTS
• SUMMARY
• REFERENCES
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3. INTRODUCTION
• According to (IASP), “pain is an unpleasant sensory & emotional experience
associated with actual or potential tissue damage.” (Zhang et al., 2017).
• Visceral pain is a global term used to describe pain originating from the
internal organs.
• It affects a significant proportion of the population with up to 25% (Moloney
et al., 2015).
• Much current understanding of pain mechanisms derives from studies of
somatic, but not visceral pain, (Cervero and Laird, 1999). WHY?
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4. Introduction Cont’d
• Visceral pain is a severe form of pain that can be exhausting and
weakening for the patient.
• However, women are subject to many forms of visceral pain (Sikandar and
Dickenson, 2012).
• Stress has long been implicated in the pathophysiology of visceral pain in
both preclinical and clinical studies (Moloney et al., 2015).
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5. Introduction Cont’d
Fig. 1: Individuals Suffering with Pain (Acid Reflux Review, 2015).
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6. STRESS
• Hans Selye defined stress as the physiological adaptive responses to
emotional or physical threats “stressors” to the organism, whether real or
perceived (Selye, 1936).
• Exposure to the stressors elicits a sequence of physiological, emotional,
and behavioural reactions that allow adequate coping with the situation
(Charmadari et al., 2005).
• Behavioural effects of the stress response include increased awareness,
improved cognition, and altered pain sensitivity (Smith and Vale, 2006).
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7. Stress Pathway
Fig. 2: Stress Pathway (Greenwood-Van Meerveld and Johnson, 2018).
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8. Hypothalamic-Pituitary-Adrenal
axis
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Fig. 3: HPA axis (Greenwood-Van Meerveld and Johnson, 2018).
8

9. VISCERAL PAIN
• Some organs are more sensitive to visceral pain than others. e.g. stomach,
bladder, and ureters (Robinson & Gebhart, 2008).
• Multiple etiologies for visceral pain include: inflammation, disruption of
normal mechanical processes, neoplasms, and ischemia (Larauche et al.,
2012).
• Visceral pain is associated with wide variety of disorders including
gallstones, acute pancreatitis, acute appendicitis, GERD (Vercellini et al.,
2009).
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10. Visceral Pain Cont’d
Anatomy
• The upper GI tract (including
esophagus and stomach) is innervated
with thoracic and lumbar afferents.
• The mid GI tract composed of the
small intestine is innervated by both
thoracic and lumbar afferents.
• The mid to lower GI tract including the
large intestine is innervated by lower
lumbar afferents and upper sacral
afferents.
• The pelvic region is innervated by
sacral afferents
(Moloney et al., 2015)
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Fig. 4: GIT Spinal innervations (Moloney et al., 2015).

11. Visceral Pain Cont’d
Characteristic
-Not all viscera have sensory innervations
-It is not linked to visceral injury
-It is referred to other locations
-It is diffuse and poorly localized
-It is accompanied by motor & autonomic reflexes (Cervero and Laird, 1999)
Comorbidities
• Psychiatric disturbances are the most frequent Comorbidity of visceral pain in
particular; anxiety and depression are the commonly reported comorbidities.
(Vermelen et al., 2014).
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12. MECHANISM OF ACTION
Stress and Peripheral Sensitization:
• Mainly a role of the corticotropin releasing factor (CRF) system.
• Stress and peripheral administration of CRF induces mast cells degranulat-
ion in the colon which can in turn lead to the development of visceral pain
(Sengupta, 2009).
• In response to an injury such as inflammation, the intestinal mucosa leads
to the release of chemical mediators (ATP, bradykinin, prostaglandins).
• which can directly stimulate afferent neuron terminals promoting the release
of algogenic substances (histamine, SP, NGF and prostaglandins), leading
to the amplification of the mechanical stimulus (Vergnolle, 2010).
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13. Mechanism of Action Cont’d
Spinal cord Plasticity and Glia Activation
• Role in the central processing of peripheral pain perception.
• Once peripheral sensitization developed, it activate the release of spinal
cord mediators like Neurokinin (NK1), Acid sensing ion channel (ASIC1A)
(Matricon et al., 2010).
• Recently, potential mechanism through which spinal sensitization may occur
in response to stress has been suggested in the form of spinal cord glia
activation (Greenwood-Van Meerveld and Johnson, 2018).
• The modulatory influence exerted by spinal microglia on visceral nociception
was supported by the findings that spinal injection of the microglia activator
induces visceral hyperalgesia (Bradesi, 2010).
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14. Mechanism of Action Cont’d
Supraspinal pain modulation
• A fine-tuning between pain facilitation and inhibition.
• Various supraspinal sites are involved in the modulation of visceral pain
signals. Rectosigmoid distension in humans activates sensory, limbic and
paralimbic regions (Zhang et al., 2011).
• Central amygdala has been implicated in the affective component of pain, It
is involved in the processing of visceral information, attention, emotion and
integrating the physical & psychological components of the stress response
(Myers et al., 2007).
• Spinal visceral nociceptive reflexes providing the basis for a mechanism by
which visceral sensations can be enhanced from supraspinal sites under
stress associated with visceral pain (Martenson et al., 2009).
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15. Neurotransmitters in Stress-Induced
Visceral Pain
• Corticosteroids
• Corticotropin-Releasing Hormone
(CRH)
• Endocannabinoids
• Gamma-Amino Butyric Acid
(GABA)
• Glutamate
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Fig. 6: Neurotransmitters in Visceral Pain (Greenwood-Van
Meerveld and Johnson, 2017).

16. Stress-Induced Animal Models
Cont’d
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Fig, 8: Rodent models of (ELS)-induced visceral P. (Greenwood-Van Meerveld and Johnson, 2017)

17. Stress-Induced Animal Models
Cont’d
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Fig. 9: Rodent model of stress-induced visceral pain in adult animals (Greenwood-Van Meerveld
and Johnson, 2017)

18. TREATMENT
• Due to its complex nature, effective treatment strategies is difficult to
identify.
• Pharmacological tools used include analgesics [opioids, non-steroidal anti-
inflammatory drugs (NSAIDS), benzodiazepines] and others (antibiotics,
laxatives, serotonin modulators).
• Antispasmodics, can also be use particularly in the case of GI visceral pain
and anti-depressants.
• However, none of the above are specific for the treatment of visceral pain
per se, and mainly target some other features associated with chronic pain
in general. (Moloney et al., 2015).
•
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19. SUMMARY
• Visceral pain is a hallmark of functional GI disorders.
• Stress has been long implicated in the pathophysiology of visceral pain, where
HPA axis is activated by both chronic adult stress and following early life (ELS)
stress.
• Mechanisms of stress-induced visceral pain include: stress and peripheral
sensitization, spinal cord plasticity & glia activation, and supraspinal pain
modulation.
• Corticosteroids, CRH, Endocannabinoids, GABA and Glutamate are some of
the Neurotransmitters in stress pathways that modulate visceral pain.
• Some experimental model to access stress-induced visceral exist. Currently,
the treatment strategies targeting visceral pain are unsatisfactory.
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20. REFERENCES
• Greenwood-Van Meerveld, B. and Johnson, A. C. (2018).
Mechanisms of Stress Induced-Visceral Pain. Journal of
Neurogastroenterology and Motility, 24: 7-18.
• Moloney, R. D., Mahony, S. M., Dinan, T. G. and Cryan, J. F.
(2015). Stress-Induced Visceral Pain: Toward Animal Models of
Irritable-Bowel Syndrome and Associated Comorbidities. Frontiers
in Psychiatry, 6(15): 1-30.
• Sikandar, S. and Dickenson, A.H. (2012). Visceral Pain – Ins and
Outs, the Ups and Downs. Current Opinion in Supportive and
Palliative Care, 6(1): 17-26.
• Zhang, F., Wu, L., Zhao, J., Lv, T., Hu, Z., Weng, Z.,…Liu, H.
(2017). Neurobiological Mechanism of Acupuncture for Relieving
Visceral Pain of Gastrointestinal Origin. Gastroenterology Research
and Practice, 2017, 1-11.
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THANKS
FOR
YOUR
AUDIENCE