The understanding of what drives chronic pain is advancing
When injury or inflammation occurs, a number of biochemical mediators, including prostaglandins, cytokines, chemokines, neuropeptides, and nerve growth factor (NGF), are released. In conditions related to chronic musculoskeletal pain, such as osteoarthritis (OA), rheumatoid arthritis (RA), tendinitis, and chronic low back pain (CLBP), these mediators have been identified as key drivers of chronic pain.1-4
These mediators perpetuate pain signaling from the periphery, leading to peripheral and central sensitization, and ultimately, contributing to chronic pain.1,5-8
CHRONIC PAIN BY THE NUMBERS
Though the magnitude and seriousness of the problem is clear, many people are unfamiliar with the underlying drivers of chronic pain. Research has shown that several biochemical mediators, including prostaglandins, cytokines (TNFα, IL-1ß, IL-6), chemokines (CCL2, CXCL1, CXCL5), growth factors (NGF, BDNF), and neuropeptides (substance P, CGRP), play a key role in the pain pathway and in making chronic pain chronic.1-3
BDNF=brain-derived neurotrophic factor; CCL2=C-C motif chemokine ligand 2; CGRP=calcitonin gene-related peptide; CV=cardiovascular; CXCL=C-X-C motif chemokine ligand; IL=interleukin; TNF=tumor necrosis factor.
Watch Chronic Pain in Action
Throughout the world, 1 in 5 people suffer from moderate to severe chronic pain.
Chronic pain can have a significant negative impact on those afflicted, with effects including sleeplessness, decreased activity, and mood changes such as depression.
Acute pain and chronic pain can have different pathophysiologies.
In acute pain, nociceptors – pain receptors in peripheral nerves – are activated when the body experiences injury or inflammation.
The nerves in the periphery send pain signals through the dorsal root ganglia to the spinal cord and central nervous system, or CNS.
When pain is acute, signaling typically stops once the cause of pain is resolved.
However, when pain is chronic—lasting more than 3 months—repeated stimulation of these sensory nerves over time causes changes to the ways the pain signals are processed, leading to a pathophysiological state where the nervous system is sensitized and the perception of pain becomes heightened.
Both the peripheral and the central nervous systems can become sensitized to pain signals.
In response to injury or inflammation, nociceptors in the periphery can become more sensitive to painful stimuli—a process called peripheral sensitization.
These sensitized nociceptors then send additional pain signals to the CNS, which can lead to the overstimulation of the CNS.
This results in central sensitization, which increases the perception of pain. As such, central sensitization leads to the perpetuation of pain.
In response to injury or inflammation, cells at the site of pain release a variety of biochemical mediators, including the neurotrophin NGF, the cytokine TNFα, the interleukins IL-1ß and IL-6, and prostaglandin E2.
These mediators bind to nociceptors in the periphery, leading to the sensitization of the pain pathway.
When the cause of pain continues over time, the persistent activation of the pain pathway leads to increased synthesis of glutamate and neuropeptides, such as Substance P, CGRP, and BDNF.
Substance P and CGRP enhance the sensitization of sensory nerves in the periphery. In the CNS, all 4 of these mediators can be released by the primary afferent neuron, subsequently binding to receptors in the dorsal horn of the spinal cord, contributing to the activation of key intracellular pathways that initiate central sensitization.
NGF, or nerve growth factor, plays a key role in the amplification of pain signals by sensitizing neurons in the pain pathway and causing the overproduction of other pain mediators.
NGF is found throughout the body. Levels of NGF increase in response to injuries or conditions associated with pain.
In the presence of some conditions associated with chronic pain like osteoarthritis, rheumatoid arthritis, gout, or chronic low back pain, there is continuous overproduction of NGF.
As a result, more NGF is available to bind to peripheral sensory nerves, increasing the number of pain signals that travel from the periphery to the CNS. This contributes to the sensitization of nerves in both the peripheral and the central nervous system, amplifying and perpetuating chronic pain.
The relationship between the periphery and the CNS provides a key insight into chronic pain: What excess NGF does here changes what happens here.
Many physiological processes drive the development of chronic musculoskeletal pain experienced in conditions such as osteoarthritis, rheumatoid arthritis, tendinitis, and chronic low back pain.
One of these processes is peripheral sensitization, a state in which nociceptors, or peripheral sensory neurons, at the site of pain become abnormally responsive to stimuli.
In response to injury or inflammation, biochemical mediators at the site of the injury are released, including prostaglandins, cytokines, and a neurotrophin called nerve growth factor, or NGF.
These mediators bind to and activate nociceptors at the site of pain. This leads to 2 key changes that affect how the peripheral nervous system responds to stimuli. One change is an increase in the number of receptors on the nociceptors. Another change is enhanced membrane permeability, which means more ions are able to pass through the membrane of nociceptors.
Both of these changes result in peripheral sensitization, where there is increased excitability of the nociceptors and additional biochemical mediators are released. As a result, nociceptors are activated by both painful and innocuous stimuli, causing increased pain signaling to the central nervous system, or CNS.
While the nervous system typically returns to a state of normal activity when the injury is resolved, if persistent signaling continues from the site of injury it may lead to hyperexcitability of neurons in the CNS, a state known as central sensitization.
There are 2 key characteristics of central sensitization that lead to a modification in the way the brain processes pain signals. The first characteristic is changes in the firing patterns of certain neurons in the dorsal horn of the spinal cord, causing them to respond to nonpainful stimuli in addition to painful stimuli. The second is increased signal transmission within the CNS from the dorsal horn to the brain. This can lead to the expansion of neuronal receptive fields, which causes pain in surrounding areas beyond the initial injury.
These 2 processes enhance the brain’s response to painful stimuli and result in painful responses to nonpainful stimuli. Over time, this state of hypersensitivity can become established within the CNS similar to the way memories are formed, leading to a sustained elevated response to painful stimuli. Ultimately, both peripheral sensitization and central sensitization may play key roles in the exacerbation of chronic pain.
Several conditions are associated with chronic musculoskeletal pain, including osteoarthritis, rheumatoid arthritis, tendinitis, and chronic low back pain.
The interaction between biochemical mediators and sensory neurons in the periphery may be an important step in the process that, over time, can lead to the exacerbation of chronic pain in these conditions.
In response to injury or inflammation, local cells release a variety of biochemical mediators that play a role in pain signaling, including chemokines, cytokines such as TNF alpha and the interleukins IL-6 and IL-1 beta, prostaglandins such as PGE₂, and a neurotrophin called NGF.
While all of these mediators may contribute to pain signaling in acute and chronic pain, NGF has been identified as a key driver of pain over time.
NGF primarily binds to the receptor TrkA, which is found on nociceptors—pain receptors in the periphery.
The NGF-TrkA complex increases pain signaling by causing changes in ion channels and by increasing the release of neuropeptides, including CGRP and substance P, by nociceptors.
These actions, along with other factors, can contribute to peripheral sensitization, a state in which nociceptors at the site of injury become hyperexcitable, making them abnormally responsive to painful stimuli.
Another key effect of NGF binding to TrkA is the release of IL-1 beta, which upregulates NGF, creating a feedback loop that results in additional NGF production.
Upregulation of NGF in the periphery may also result in the increased release of mediators in the CNS, or central nervous system, resulting in a cascade of events that may contribute to chronic pain.
In the dorsal horn of the spinal cord, mediators are released from the primary afferent terminals and activate neurons in the spinal cord, which receive pain signals from the periphery.
Ultimately, these mediators activate specific neurons that convey pain signals to the brain.
Over time, these actions can play a critical role in causing central sensitization—a state in which neurons in the CNS become hyperexcitable.
These neurons then experience increased sensitivity to sensory inputs, contributing to the heightened perception of pain.
When an injury or inflammation is chronic, it leads to sustained overproduction of NGF in the periphery.
Over time, excess levels of NGF may lead to amplified pain signaling and sensitization of the peripheral and central nervous systems.
In summary, NGF and other mediators play an essential role in driving chronic pain, showing that what excess NGF does in the periphery can change the perception of pain in the CNS.
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