A ‘Never-Ending’ Loop of Pain and Psychological Stress

Sahithi Yeturu | SQ Vol. 20 Research Features (2022-2023)


Nearly everyone has experienced an episode of sharp, severe pain, maybe upon getting a cut, breaking a bone, or dislocating a shoulder. This sudden, short-lived sensation is known as acute pain, a physiological response to the brain detecting pain-inducing stimuli, such as tissue damage, inflammation, localized injury, or illness. Acute pain generally lasts less than six months1 and usually resolves naturally through an innate immune response or conservative treatment, such as physical therapy, injections, or chiropractic care. However, one in five American adults develops a more intense and persistent pain that lasts well beyond the typical recovery period of acute pain, involving long-term remodeling of the nervous system2. For people with chronic pain, intense pain signals are triggered in the absence of painful stimuli and lead to hypersensitivity in nociceptors, or pain-detecting sensory receptors. 


Patients diagnosed with chronic pain often struggle with fulfilling daily activities, such as household and workplace responsibilities, as the fear of potentially aggravating their pain can impel them to avoid social and physical activities. These interferences with their personal and professional lives can cause unwanted frustration and reduce their self-esteem, posing a higher risk for comorbid anxiety and depression in chronic pain patients. 


In her literature review, Leslie Ngo, a fourth-year undergraduate at UC San Diego, explores the intricate link between chronic pain and mental health. Ngo, who is majoring in Earth Sciences, aspires to work in the field as a geologist, however, her interest in exploring the pathophysiology of chronic pain and its associated psychological comorbidities stems from her own journey coping with chronic knee pain for the past six years. She faced difficulty with basic movements such as climbing up stairs or walking in between classes, disrupted sleep, and lower energy levels during the day, which gradually took a toll on her productivity and independence. She hopes that her research will improve public understanding of the emotional impact of living with an invisible condition. Ngo’s analysis of the biological intersections between chronic pain and anxiety and depression evidences the importance of interdisciplinary care to comprehensively treat chronic pain.


To develop effective treatment plans for chronic panic, it is important to understand the intricacies of the pain cycle. Pain perception starts at the level of nociceptors, specialized sensory neurons that detect sensory changes from pain-inducing stimuli3. When activated, nociceptors generate an action potential, an electrical impulse caused by the flow of ions in and out of the neuronal cell body, transmitting a signal. Pain signals can be excitatory or inhibitory, and they are carried between different brain structures through a variety of neurons. These signals are facilitated by small signaling chemicals in the brain known as neurotransmitters3. As the signal travels down the nociceptor via the axon terminal, neurotransmitters are released into the synapse, the contact point between two communicating neurons. The ejected neurotransmitters interact with receptors on the postsynaptic neuron, allowing for the transmission of the pain signal. 


After the sensory stimulation of a nociceptor, signaling is dictated by two separate pathways: ascending and descending. The two pathways are a pivotal part of the central nervous system (CNS), the neuronal network within the brain and spinal cord connecting sensation with perception. The ascending pathway starts when nociceptors send a neuronal signal that travels to the dorsal horn of the spinal cord to process the somatosensory signals. The neurons carrying the signal branch off, and the pain signal ascends through nerve fibers in the brain stem, eventually projecting to the thalamus. The thalamus serves as a sensory relay station in the brain, sending the signals to the primary and secondary somatosensory cortices (S1 and S2) that work together to process and store experiences, such as the emotions associated with the pain4. While the ascending pathway primarily helps with processing pain signals, the descending analgesic pathway uses the periaqueductal grey area (PAG) in the brain to help regulate the intensity of these pain signals. Stimulated PAG neurons activate serotonin-releasing neurons, which project onto inhibitory neurons in the dorsal horn5. Activation of these inhibitory neurons causes the initial pain signal to be suppressed, reducing the pain sensations.


Neurotransmitter release into the synaptic cleft is vital for neuronal communication and signaling. In her review, Ngo focuses on two particular neurotransmitters—glutamate and GABA—that are vital in pain perception and anxiety. Glutamate, an excitatory neurotransmitter, binds to ion channels on the membranes of nociceptors involved in the ascending pathway. Because glutamate is excitatory, higher levels of glutamate can lead to rapid unwanted neurotransmission of pain. On the other hand, excitatory signaling within nociceptive neurons is partially inhibited by GABA, which interacts with receptors within the dorsal horn to gatekeep pain signals from nociceptors from connecting to the CNS6. Reduced GABA activity in the dorsal horn allows pain signals to enter the CNS, triggering neuronal sensitization. In addition to its role in the descending pathway, GABA is also involved in regulating emotional networks. Within the amygdala, the brain region that integrates emotions and behavior, GABA-producing neurons decrease pain-associated fear. Studies also point to higher amygdala activity in subjects with depressive disorders, highlighting the biological overlap between emotion and pain processing that are crucial to consider when forming a treatment plan for chronic pain7


Many pharmacological interventions have been developed to manage pain, one being N-methyl-d-aspartate (NMDA) receptor antagonists. Excessive glutamate causes overactivity in NMDA receptors. This overactivity causes neurons within the spinal cord to become hypersensitive to non-noxious stimuli, such as a harmless touch. To reduce pain signal transmission, NMDA receptor antagonists bind to NMDA receptors to inhibit receptor activity, reducing the intensity of pain signals. Historically, NMDA antagonists have been prescribed alongside opioids, which can indirectly inhibit NMDA receptor activity by decreasing levels of glutamate. When opioid receptors are activated, a protein cascade prevents the influx of calcium ions into the neuronal cells, preventing the neuron from releasing glutamate, and thus reducing the intensity of the pain signal8. However, long-term opioid usage has been associated with a high risk of physiological addiction to the medication. As a result, opioids are not considered a safe long-term pharmacological treatment that is required to treat chronic pain. 


More recently, antidepressants have emerged as a low risk pharmacological intervention that can help address both the physiological and psychological aspects of pain. Antidepressants increase neurotransmitter-based regulation of activity in the amygdala, reducing the intensity of fear based signaling pathways9. Additionally, as Leslie outlines in her review, antidepressants also increase levels of the neurotransmitter norepinephrine in the descending pathway. Norepinephrine binds to receptors within the dorsal horn that inhibit the release of glutamate, preventing the transmission of pain signals. Although pain medication has tremendous potential to alter signaling pathways, additional forms of care are required to treat the mental tax caused by chronic pain.


A promising avenue for treatment is to supplement medication with psychological therapy. One of the most promising psychotherapies that has emerged to effectively treat chronic pain is cognitive behavioral therapy (CBT), an evidence-based treatment that aims to identify patterns of unpleasant or harmful thoughts and attitudes. The most prevalent symptoms associated with anxiety and depression are repeated negative cognitions or thoughts, which often translate to self-restricting and undesirable behaviors. Chronic pain patients commonly exhibit fear-avoidance beliefs, where patients assume that physical exercise could exacerbate pain and therefore avoid engaging in physical activities. CBT specialists help patients recognize these harmful cognitive patterns and develop healthier habits by adjusting their perception of physical activity. 


In addition to reconstructing these fear-based cognitions and behaviors, psychological therapies can encourage small lifestyle changes that encourage a self-nurturing mindset. Mindfulness-based techniques like yoga or meditation can complement CBT and help reduce stress and elevate mood. In her review, Ngo outlines studies that show how yoga encourages the neurochemical release of GABA, which can activate the descending pathway to reduce pain signals. These studies also show that yoga was associated with a decreased release of cortisol, a stress hormone. Addressing these maladaptive thoughts and attitudes can alleviate the physical experience of pain and comorbid anxiety at both the cognitive and physiological levels. Significant progress can result from educating patients, guiding them through anxiety-inducing activities, and encouraging them to work towards a small yet achievable fitness goal.


Contemporary pharmacological and psychological treatment options certainly provide proof of substantial progress in the field of pain medicine, but it is essential to recognize that each patient diagnosed with chronic pain experiences the condition in a subjective and very personal. Ngo’s review is most definitely a starting point to better understand how to tailor treatment combinations to help improve a patient’s quality of life. Ngo believes further research is required to elucidate the structural and functional changes within the brain that may be associated with neuronal sensitization during the transition from acute to chronic pain. In unearthing this complex interplay, she hopes that those suffering from chronic pain like herself can more easily access psychotherapeutic treatments to reduce medical biases toward pharmacology and instead help patients develop more sustainable lifestyles and practices.



  1. Acute vs. Chronic Pain. Cleveland Clinic https://my.clevelandclinic.org/health/articles/12051-acute-vs-chronic-pain#:~:text=Acute%20pan%20usually%20doesn
  2. One in five American adults experience chronic pain. ScienceDaily. https://www.sciencedaily.com/releases/2021/04/210420092901.htm.
  3. How We Feel Pain. The National Vulvodynia Association. https://www.nva.org/learnpatient/how-we-feel-pain/
  4. Neuroanatomy, Somatosensory Cortex. PubMed. https://www.ncbi.nlm.nih.gov/books/NBK555915/.
  5. Periaqueductal gray neurons project to spinally projecting GABAergic neurons in the rostral ventromedial medulla. PAIN. https://doi.org/10.1016/j.pain
  6. Inhibitory regulation of the pain gate and how its failure causes pathological pain. PAIN. https://doi.org/10.1097/j.pain.0000000000000139.
  7. Adolescents With Major Depression Demonstrate Increased Amygdala Activation. Journal of the American Academy of Child & Adolescent Psychiatry. https://doi.org/10.1097/00004583-201001000-00008.
  8. Molecular Mechanisms of Opioid Receptor-Dependent Signaling and Behavior. National Institues of Health. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698859/
  9. How do antidepressants work? New perspectives for refining future treatment approaches.The Lancet Psychiatry. 4(5):409–418. https://doi.org/10.1016/s2215-0366(17)30015-9