Nerve growth factor (NGF)
is one of the key drivers
of chronic pain caused by conditions such as
osteoarthritis (OA)

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.

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.