by Beatrice Awasthi
figures by Allie Elchert

Millions of Americans struggle with chronic pain. While the pain sometimes has a clear source—for instance, an arthritic joint or a damaged tendon—oftentimes, people feel pain without any obvious signs of damage at all. This can be extremely distressing, as such patients may deal with stigmatization or invalidation of their pain by others who suggest that the pain is imagined.

Notably, in recent years, the field of pain research has uncovered a great deal of information about underlying physiological causes of chronic pain. This new wealth of information is especially relevant to chronic pain patients because it demonstrates that for many, their pain is not imagined, but rather caused by sensitization of the nervous system due to physical changes in neurons, the cells that make up the nervous system and play a key role in sensation. When neurons responsible for sensing pain become sensitized, it means that they sense pain in situations where they previously would not have. Accordingly, development of treatments focused on neuronal desensitization could help to alleviate pain for a subset of chronic pain patients.

Overview of the nervous system and neuronal biology

The nervous system can be broadly divided into two parts: the central nervous system, which comprises the brain and spinal cord, and the peripheral nervous system, which comprises all neurons outside the brain and spinal cord. Neurons of the peripheral nervous system mediate communication between the central nervous system and the limbs and organs of the body (Figure 1). Resting neurons exist in an electrically charged state due to a specific balance of charged molecules called ions that exist both inside and outside the neuron. A structure called the cell membrane encloses the neuron and prevents the ions from crossing freely, which helps to maintain the neuronal charge, also known as the membrane potential. 

Figure 1: The nervous system is composed of nerves that extend throughout the body. These nerves are either part of the central nervous system or the peripheral nervous system. The central nervous system is made up of the brain and spinal cord, while the peripheral nervous system refers to the nerves that extend throughout the rest of the body.

Three primary components make up a neuron: the cell body, dendrites, and axons. Neurons receive signals from other neurons via specialized receptors on their dendrites and release signaling molecules called neurotransmitters from the ends of their axons (axon terminals). The receptors are part of special channels, which normally exist in a closed state so that no ions can flow through. When a neurotransmitter binds to a receptor, the receptor’s shape changes, causing the channel gate to open and enabling ions to flow through, thus changing the electrical state of the neuron. Such a change in electrical state is known as an action potential, which can then stimulate further neurotransmitter release. The newly released neurotransmitters then bind to receptors on a neighboring neuron to pass the signal along. Most neuronal axons split into numerous branches, which allows a single neuron to connect via its axon with the dendrites of thousands of other neurons (Figure 2).

Figure 2: Neurons are composed of a cell body, dendrites, and an axon, which branches into several fibers. Specialized receptor channels control the flow of electrically charged ions between the outside and inside of the neuron and maintain the electrical state of the neuron. In response to a change in the electrical state, neurotransmitters are released from the axon terminals and bind to receptors on the dendrites of a neighboring neuron. This causes a similar change in the electrical state of the neighboring neuron, leading to subsequent neurotransmitter release and propagation of the signal to the next neuron.

The cell bodies of peripheral neurons reside in either the brain or the spine. The axon fibers protruding from these neurons can control sensory functions. Sensory neuronal fibers relay information about external stimuli (i.e. pressure, temperature, or various chemicals) to the central nervous system via signaling mediated by neurotransmitters. These external stimuli are detected by specialized receptors on the sensory fibers that are specific to each stimulus type.

Neurobiology of chronic pain

Sensory fibers that specifically function to signal the presence of a noxious, or painful, stimulus are known as nociceptors. Painful stimuli can be mechanical (an external force), thermal (such as high temperatures), or chemical (such as wasabi). Nociceptors have a high threshold for activation, meaning that an intense stimulus is required to induce enough receptor activation to generate an action potential. In the situation of acute, non-chronic pain, a given stimulus elicits nociceptor activation and the consequent sensation of pain. Following removal of the stimulus, the pain sensation calms down. 

Unfortunately, sometimes the sensation of pain becomes chronic. In such cases, a person might feel heightened pain in response to a stimulus that was previously only mildly painful or pain in response to no stimulus at all. The biological basis of this increased sensitivity lies in physiological changes induced in neurons in response to extended painful signaling. 

In some cases, these changes occur in the nociceptors themselves. When tissue damage occurs—for example, excessive mechanical force causing a tendon to rupture—nociceptors are activated in response to the stimulus, which notifies the central nervous system that something is wrong. Simultaneously, both the damaged tissue and the nociceptors release inflammatory signals to recruit immune cells. These inflammatory signals are crucial because they stimulate a healing response in the damaged tissue. However, they also bind to receptors on the nociceptors and induce a variety of changes within the nociceptors themselves that sensitize them to external signals. One example of this is lowering the change in membrane potential required to induce an action potential, thus making the neurons more easily stimulated. For example, the heat threshold of a nociceptor might be lowered to body temperature, leading the nociceptor to send pain signals in response to normal body temperature. In such a case, pain sensation would be transmitted from that nociceptor all the time, not just in response to a higher temperature that would normally stimulate it (Figure 3).

Figure 3: Tissue damage leads to the release of inflammatory mediators that can induce a variety of changes in nociceptors. These can include a) chemical modification of channels by special proteins called kinases that make the channels more sensitive to stimuli and b) changes in the number of receptors on the neuronal surface, leading to an increased ability to bind external signals and consequent increased sensitivity to these signals.

Changes within the central nervous system can also contribute to chronic pain sensations, a phenomenon known as central sensitization. In central sensitization, the neurons in the central nervous system begin generating action potentials even in the absence of stimuli from nociceptors due to changes within the neurons themselves. For example, a higher number of ion channels in spinal cord neurons has been found to be associated with a hypersensitivity to cold in laboratory animal models. This is likely because more ion channels enables a faster change in the electrical state of the neuron. Another potential mechanism of central sensitization is the reorganization of synapses in the spinal cord that can occur after a prolonged period of nociceptor signaling, leading to the inappropriate transmission of pain signals within the central nervous system. Such changes can result in feelings of pain both after, and in some cases, beyond the area where the original injury occurred. 

Can the nervous system be desensitized?

While nerve sensitization can be challenging and frustrating to treat, a variety of external neuromodulation treatments have the potential to intercept pain signaling pathways to help manage uncontrolled pain. For instance, the infusion of ketamine, which blocks receptors involved in painful signaling between nociceptors and the central nervous system, is sometimes used to treat pain disorders like complex regional pain syndrome. One of these receptors is the N-methyl D-aspartate (NMDA) receptor, which plays a major role in transmitting painful signals within the nervous system and is often inappropriately activated in chronic pain. Drugs like gabapentin and Lyrica are also used to treat nerve-related pain by blocking pro-pain signaling (Figure 4). Another option is the use of a spinal cord stimulator, which triggers non-nociceptive signaling. The mechanism of action of spinal cord stimulation is not fully understood, but it is likely that it works partly by stimulating the release of neurotransmitters that inhibit nociceptors’ signaling. Additionally, for individuals with movement limitations due to pain who can tolerate a certain level of movement, movement within a pain-free range can reduce nociceptive signaling and help to calm the nervous system down. Complexity of movements can be slowly increased as tolerated. Here, cognitive behavior therapies and retraining to help address fear avoidance (fear of specific movements due to pain) can be helpful, as expectation of pain can increase the sensation of pain.

Figure 4: Drugs like gabapentin and ketamine can be used to treat nerve-driven pain. Tissue damage leads to the increased release of pain signals within the nervous system, which activates receptors like the NMDA receptor on neighboring neurons, leading to propagation of the pain signal. Both gabapentin and ketamine function, in part, by disrupting the activity of the NMDA receptor. Gabapentin can inhibit NMDA receptors by reducing the stability and delivery of the NMDA receptor to the neurons’ surface, while ketamine directly blocks the receptor.

Looking Forward

The complexity of pain and the involved signaling pathways can make it challenging to pinpoint the cause of patients’ pain, which in turn can render pain extremely difficult to treat. It is important to remember that the absence of obvious tissue injury does not mean that pain is simply imagined, as pain due to nervous system dysregulation is as real as acute pain due to tissue injury, and can be disabling. Sensitization-associated pain should be taken seriously, as effective treatments can only be administered if it is properly diagnosed. Proper diagnosis and treatment can go a long way in restoring a patient’s quality of life, alleviating limitations, and lifting the emotional burden that comes with living in chronic pain.

Beatrice Awasthi is a graduate student in the Biological and Biomedical Ph.D. program at Harvard Medical School. She studies signaling in colon and pancreatic cancer.

Allie Elchert is a third-year Ph.D. student in the Biological and Biomedical Sciences program at Harvard Medical School.

For more information:

  • Neurons are not the only cells in the nervous system controlling chronic pain. Cells called microglia, which reside in the brain and spinal cord and play a key role in maintaining nervous system function, are also known to contribute to chronic pain. Check out this article and this article to learn more about how they do this.
  • Read more about the interaction between the nervous system and the immune system—the neuroimmune interactome—here.
  • Check out this review to learn more about treatment options for neuropathic pain, including pharmacological (drug), interventional (i.e. surgery), physical (i.e. physical therapy), and psychological approaches.

2 thoughts on “Sensitization: Why everything might hurt when it looks like nothing is wrong

  1. Amazing article, i read entire. can i get answer
    What pain, emotional or physical, have you experienced lately?

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