Chronic Pain in Brain: Structural and Functional Changes

Chronic Pain: Structural and Functional Changes in Brain Structures and Associated Negative Affective States – free full-text article /PMC6650904/ – Jul 2019

This is an extremely thorough article covering many aspects of chronic pain. I’ve tried to cover only key parts and avoid lengthy descriptions of scientific details. After each section, I show a link to the complete section with all its details.


Chronic pain is a condition in which pain progresses from an acute to chronic state and persists beyond the healing process.

Chronic pain impairs function and decreases patients’ quality of life.

In this review, we summarize the results of previous studies, focusing on the mechanisms underlying chronic pain development and the identification of neural areas related to chronic pain.  

We review the association between chronic pain and negative affective states. Further, we describe the structural and functional changes in brain structures that accompany the chronification of pain and discuss various neurotransmitter families involved. Our review aims to provide guidance for the development of future therapeutic approaches that could be used in the management of chronic pain.

1. Introduction

Pain is a serious and common global medical problem that can cause long-term disability.

As the experience of chronic pain is associated with activity in multiple networks in the central nervous system (CNS), chronic pain is considered a CNS disorder.

Patients who suffer from painful conditions may demonstrate various clinical outcomes. In most cases, pain-inducing conditions resolve over time, as the body goes through the normal healing process. In a subset of cases, pain progresses into a chronic condition in which pain persists for many years

The primary goal of this review is to explore the mechanisms of development of chronic pain.

We review the current knowledge of neural areas related to chronic pain, the relationship between chronic pain and negative affective states, structural and functional changes that occur in brain structures during the development of chronic pain, and various neurotransmitter systems involved in the chronification of pain.

2. Pain Pathways and Mechanisms of Chronic Pain

Pain can be classified into three major types:

  1. Nociceptive,
  2. inflammatory, and
  3. neuropathic pain.

Nociceptive pain is the response of sensory systems to actual or potentially harmful stimuli detected by nociceptors around the body.

Inflammatory pain is associated with tissue damage and the resulting inflammatory process, which may lead to responses such as hyperalgesia, allodynia, and sympathetically maintained pain .

Neuropathic pain is a localized sensation of unpleasant discomfort caused by damage or disease in the peripheral and/or central nervous system that persists after a primary lesion or dysfunction.

Neuropathic pain may be associated with allodynia, which refers to pain sensitization to stimuli that do not normally provoke pain (non-painful stimulation).

Hyperalgesia refers to an abnormally increased sensitivity to pain, which is associated with hypersensitivity to stimuli.

Primary hyperalgesia occurs directly in damaged tissues, whereas secondary hyperalgesia occurs in areas surrounding damaged tissues due to pain-related mediators binding to receptors around the injury site, causing sensitization of adjacent uninjured tissues to mechanical stimuli.

Pain pathways comprise a complex sensory system, which is activated to provide protective responses to noxious stimuli.

Pain is actually designed to protect us – and it definitely does, because the rare people who cannot feel pain suffer many serious injuries because they can’t feel damage to tissue, like leaving a hand on a hot stove.

To see descriptions of the intricate biology of these pathways in detail: see

3. Pain and Negative Affective States

Brain structures, including the

  • primary somatosensory cortex,
  • secondary somatosensory cortex,
  • anterior cingulate cortex (ACC),
  • prefrontal cortex (PFC),
  • insular cortex,
  • amygdala,
  • thalamus,
  • cerebellum, and
  • PAG,

have been identified as regions associated with the perception of pain.

We can see that the sensation of pain affects almost every part of the brain and writing it off as “catastrophizing” seems ridiculous.

The ventral tegmental area (VTA) and NAc, structures comprising the mesolimbic reward circuit, are involved in chronic pain.

The prefrontal region and limbic system (ACC, amygdala, VTA, and NAc) are associated with affective aspects of pain and regulate emotional and motivational responses

These brain regions are not activated separately; they are functionally connected and contribute in a combined fashion to pain processing. Changes in emotional and motivational cues can affect the intensity and degree of pain experience

The intensity and degree of pain experience can affect changes in emotional and motivational cues.

A number of neuroimaging studies have demonstrated that morphological changes in corticolimbic structures and emotional systems are associated with persistent pain.

In summary, functional and structural changes in the corticolimbic system and corticolimbic interactions in patients with chronic pain can contribute to emotional and cognitive problems

As pain develops into a chronic condition, negative emotional states may be accompanied by other emotional disorders such as anxiety, anhedonia, cognitive deficits, sleep disturbances, and suicide

A recent review indicated that chronic pain itself is an important independent risk factor for suicidality regardless of type and concluded that depressive symptoms, anger problems, and harmful habits are general risk factors for suicidality in patients with chronic pain

Chronic pain and various affective disorders are often managed poorly.

So now they call it “poor management” when doctors refuse patients their pain-relieving medications. To me, it borders on malpractice when doctors de-prescribe medication that is working well.

Restricting a necessary medication and causing a dramatic decrease in patient functionality for no medical reason cannot be the proper “practice of medicine”. It’s more like practicing torture.

For more detail in this section, see

4. Pain and Long-Term Functional Changes in Corticolimbic Structures

Structural and functional plasticity in the corticolimbic circuitry accompanies the transition from acute to chronic pain. When nociceptive signals persist, the corticolimbic circuitry stays activated.

Corticolimbic structures that are associated with pain and their long-term functional changes are described below (Table 1).

Table 1
Corticolimbic structures associated with chronic pain.

Brain Structures Location Function
Medial prefrontal cortex Located in the frontal lobe Decision making, self-control, regulation of emotion, processing of risk and fear, and regulation of amygdala activity
Amygdala Located in the frontal portion of the temporal lobe, close to the hippocampus Memory modulation, decision-making, reward, and emotional responses
Periaqeuductal gray Located around the cerebral aqueduct within the tegmentum of the midbrain Autonomic function, motivated behavior, behavioral responses to threatening stimuli, and primary control center for descending pain modulation
Anterior cingulate cortex Located in the frontal part of the cingulate cortex Autonomic functions, attention allocation, reward anticipation, decision-making, ethics and morality, impulse control, emotion, and registration of physical pain
Hippocampus Located in the medial temporal lobe Consolidation of memories, emotion, navigation, spatial orientation, and learning
Nucleus accumbens Located in the basal forebrain Cognitive processing of motivation, aversion, reward, reinforcement learning, and significant role in addiction

4.1. Prefrontal Cortex

The mPFC is an important region for top-down cognitive control over emotion-driven behaviors. The mPFC is a critical region involved in emotional and cognitive processing in chronic pain.

4.3 Anterior Cingulate Cortex

The ACC is associated with affective and motivational aspects of pain.

In other words, the pain makes us “feel bad” and we are highly motivated to avoid any activities that aggravate it.

The ACC is involved in the processing and modulation of pain. Nociceptive inputs are sent from the medial thalamus to ACC and combined with motivation and affective information received from other areas of the brain, such as the insular cortex, mPFC, and BLA. 

The ACC then generates affective and motivational pain responses through its projections to the amygdala, NAc, and mPFC. 

The activation of ACC-PFC-PAG circuity and increased activity in the ACC is associated with negative emotions.

4.4 Amygdala

The amygdala is associated with emotions and affective disorders. 

The amygdala is an evolutionary holdover, sometimes called the “lizard brain” because its functions are so crude and primitive. It’s intended to signal danger and initiate evasion, a biological “panic button” that squirts out a burst of stress hormones when provoked by fear.

In that process, it overrides the “thinking” parts of our brain (which would be too slow to react), overextends our physical capacity, disregards immediate damage, and summons a supreme bodily effort to evade the perceived danger in a “do or die” effort.

Studies have reported activation of the amygdala in pain states, suggesting that the amygdala plays an important role in emotional affective aspects of pain.

The amygdala receives cortical and thalamic inputs, and the lateral/basolateral (LA/BLA) complex of the amygdala adds emotional and affective context to sensory information. 

This information is then sent to the central nucleus of the amygdala, which comprises γ-aminobutyric acid (GABA)-ergic neurons and regulates fear and pain.

Preclinical studies have demonstrated that neuronal excitability is increased in the central nucleus of the amygdala in neuropathic pain.

This makes it sound like an aberration is causing pain when it’s actually a powerful survival instinct. In nature, pain signals danger, so the amygdala is designed to create an extremely unpleasant fear that’s meant to get us into our body’s “emergency mode”.

Then the article talks about other brain regions affected by pain:

4.4. Hippocampus

The hippocampus is part of the limbic system, which plays an important role in declarative and episodic memory

4.5. Nucleus Accumbens

The NAc is a forebrain structure that integrates cortical and affective information and assigns motivation and value for the selection of appropriate behavioral responses.

4.6. Periaqueductal Gray Matter

The PAG is located in the brain stem and is divided into three subregions: ventrolateral, lateral, and dorsolateral. The PAG plays an important role in both the ascending and descending modulation of nociception and regulates other autonomic and emotional behaviors.

For more detail on this section, see

5. The Role of Neurotransmitters in Chronic Pain

Neurotransmitters are chemical substances that mediate transmission of impulses across the synapse. The transmission of neuronal signals across the synapse is initiated with the release of neurotransmitters from the presynaptic neuron.

5.1. Neuropeptides

Neuropeptides are a family of neurotransmitters that are relatively large molecules from a structural perspective. Neuropeptides constitute a diverse group of signaling molecules 

5.2. Glutamate

Glutamate is an excitatory neurotransmitter which plays an important role in neuronal activation. Glutamate mediates synaptic transmission of sensations such as pain and itchiness. Glutamate also participates in the generation of long-term plastic changes in the cortex and is a key player in central sensitization

5.3. Gamma-Aminobutyric Acid (GABA)

GABA is an inhibitory neurotransmitter in the CNS that reduces neuronal excitability and regulates muscle tone. GABA is involved in pain modulation by regulating the transmission of nociceptive signals

5.4. Neurotrophic Factors

Neurotrophic factors are molecules that regulate the growth of neurons and contribute to the proliferation of nociceptive axons and terminals in peripheral tissues, which may result in persistent pain conditions

5.5. Nitric Oxide

NO is a freely diffusible, soluble gas with a half-life of seconds [100]. NO is synthesized by nitric oxide synthase (NOS) and is primarily regulated by the expression and activity of NOS 

5.6. Opioid Peptides

Opioid peptides are a family of neuropeptides that bind to opioid receptors, including μ, δ, and κ receptor subtypes 

5.7. Endocannabinoids

Cannabinoids are a class of neurotransmitters present in pain signal transduction pathways. After injury, neural and nonneural cells release arachidonic acid derivatives known as endocannabinoids [107]. Endocannabinoids regulate neural conduction of pain signals by attenuating sensitization and inflammation via the activation of cannabinoid receptors type 1 and type 2 (CB1 and CB2)

5.8. Leptin and Orexin

Leptin is a peptide produced by adipose tissue. The concentration of leptin is regulated by nutritional state. Leptin expression is increased following food intake and suppresses appetite, whereas leptin expression is decreased with fasting. Although leptin is known to be involved in the modulation of pain signals, its role in the pathogenesis of neuropathic pain is controversial.

5.9. Melatonin

Melatonin is a hormone produced from tryptophan in the pineal gland. It is involved in the control of circadian rhythms and associated physiological responses such as sleep, anxiety, and pain [118]. The development of chronic pain syndromes is associated with the desynchronization of circadian and biological rhythms. The mechanisms underlying the analgesic effects of melatonin include the involvement of β-endorphins, GABA receptors, opioid 1-receptors, and the NO-arginine pathway

For more detail about this section, see

6. Treatment of Chronic Pain

The prevention and treatment of chronic pain may be achievable with pharmacological and/or psychological interventions.

Despite the progress made in understanding how chronic pain occurs, the development of effective drugs capable of controlling chronic pain remains a challenge.

Pharmacological agents commonly used in primary care settings include

  • gabapentin and pregabalin, which decrease calcium-mediated release of glutamate and other neurotransmitters.
  • NMDA receptor antagonists (such as dextromethorphan and ketamine) and
  • antidepressants (such as serotonin and norepinephrine reuptake inhibitors and tricyclic antidepressants).

Other pharmacological interventions targeting a variety of ion channels, neurotransmitters, and receptors are under investigation for prevention or reversal of the reorganization of chronic pain pathways.

For more detail, see

6. Treatment of Chronic Pain

Psychological interventions for chronic pain include operant behavioral therapy, cognitive behavioral therapy, and motivational interviewing.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique used to reduce chronic pain by directly altering brain activity by electrical stimulation.

Integrative strategies such as exercise, yoga, and nutrition have been suggested to have analgesic effects.

This is a rare realistic judgment, stating that integrative (alternative medicine) approaches are only “suggested” to alleviate chronic pain.

For effective treatment of chronic pain, various therapeutic approaches described above should be used in combination.

However, despite the application of several therapeutic methods, some patients will experience persistent pain, which affects quality of life.

For more detail, see

7. Discussion

Chronic pain is a critical medical problem worldwide, characterized by a high prevalence and significant cost. If pain becomes chronic, it can significantly reduce quality of life and cause

  • depression,
  • suicide,
  • insomnia,
  • impaired cognitive function,

and other deleterious effects.

The development of chronic pain is associated with synaptic plasticity and changes in the CNS and various neural areas that modulate pain. Chronic pain entails structural and functional changes in corticolimbic brain regions.

Changes related to chronic pain can induce negative affective states such as depression, anger, and anxiety, underpinned by common neuroplasticity changes in chronic pain and negative affective states.

Pain has several important dimensions, including

  • sensory,
  • emotional, and
  • cognitive dimensions.

The sensory dimension of pain involves how we perceive pain signals and the amount of pain we recognize.

The emotional dimension of pain indicates how we feel about experiencing pain.

The cognitive dimension of pain entails how we interpret pain and how we respond to pain stimuli.

8. Conclusions

Chronic pain is one of the most intractable clinical problems faced by clinicians and can be physically and emotionally debilitating.

Combinations of treatments are currently used for treating chronic pain, but a subset of patients experience persistent non-endurable pain.

Exactly! This is called “intractable” pain, the kind that is literally unbearable and can lead to suicide if left untreated.

Congratulations if you’ve read this whole ~2500-word post!

2 thoughts on “Chronic Pain in Brain: Structural and Functional Changes

  1. Bob Schubring

    An ignored area of research is Endorphin Depletion. Endorphin was first discovered ib the 1980s and is the pentapeptide of morphine. The enzymes that deactivate morphine into endorphin and reactivate endorphin into morphine are poorly understood. However, the transition from long-term acute pain into chronic pain likely involves the depletion of endorphin reserves, as all available morphine is used in the periaqueductal grey matter. Associated hyperalgesia may actually be the result of endorphin depletion, and not from treatment with opiate drugs and prodrugs that give rise to the endorphin precursor Morphine.

    This is an underexplored potential side effect of treating pain with synthetics like Fentanyl. The fentanyl metabolites can not become endorphin because they are not morphine. The body can remain endorphin deficient while the pain persists.

    Liked by 1 person


Other thoughts?

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.