NOCICEPTORS: PAIN RECEPTORS - GEOGRAFÍA - 2025

The nociceptors or pain receptors are receptors on the skin, joints and organs that capture pain. These receptors are free nerve endings found in the skin, muscles, joints, bones, and viscera. They are also called noxious stimulus detectors, as they are able to distinguish between harmless and harmful stimuli.

Nociceptors are found at the end of the axons of sensory neurons, and they send painful messages to the spinal cord and brain. Noxious stimuli are those that damage tissues and activate nociceptors.

Therefore, nociceptors are sensitive receptors that pick up signals from damaged tissue or the threat of damage. In addition, they respond indirectly to chemicals released by injured tissue.

What is pain and what is it for?

4 Models for the structure of the sensory system in humans. Nociceptors are shown as type A free nerve endings. (Source: Shigeru23 via Wikimedia Commons)

Pain is a feeling of discomfort that occurs when stimuli are received that are harmful to the body. Pain analysis is extremely complicated. Being aware of pain and reacting emotionally to it are processes that are controlled inside our brain. Most of the senses are primarily informational, while pain serves to protect us.

Pain has a survival function for living beings. It serves to become aware of potentially harmful stimuli and to get away from them as soon as possible. Therefore, people who do not feel pain can be in serious danger, as they can be burned, cut or hit by not moving away in time.

These nerve endings have been found to possess TRP (transient potential receptor) channels that detect damage. A wide variety of noxious stimuli are interpreted by these receptors. They do this by initiating action potentials in the pain nerve fibers that reach the spinal cord.

The cell bodies of the nocieptors are located mainly in the dorsal root and in the trigeminal ganglia. Whereas in the central nervous system there are no nociceptors.

Anatomy of the nociceptors

Nociceptive route. Transmission of pain from the nociceptive receptor to the cerebral cortex. Source: Bettina Guebeli via Wikimedia Commons)

Nociceptors are difficult to study and much remains to be learned about pain mechanisms. However, nociceptors in the skin are known to be an extremely heterogeneous group of neurons.

They are organized into ganglia (groups of neurons) that are located outside the central nervous system, on the periphery. These sensory ganglia interpret external noxious stimuli from the skin up to meters away from their cell bodies.

However, the activity of the nociceptors does not in itself produce the perception of pain. For this, the information from the nociceptors must reach the higher centers (central nervous system).

The speed of pain transmission depends on the diameter of the axons (processes) of the neurons and whether they are myelinated or not. Myelin is a substance that covers axons and facilitates the conduction of nerve impulses in neurons, making them go faster.

Most nociceptors have small diameter unmyelinated axons, known as C fibers. They are organized into small groups surrounded by Schwann (support) cells.

Rapid pain, therefore, is related to the nociceptors of the A fibers. Their axons are covered with myelin and carry information much faster than the previous ones.

The nociceptors of the A fibers are sensitive mainly to extreme temperatures and mechanical pressures.

Types of nociceptors and functions

Not all nociceptors respond in the same way and with the same intensity to noxious stimuli. They fall into several categories, based on their responses to mechanical, thermal, or chemical stimulation released by injuries, inflammation, or tumors.

As a curiosity, a distinctive characteristic of nociceptors is that they can be sensitized by prolonged stimulation, beginning to respond to other different sensations.

- Skin or cutaneous nociceptors

This type of nociceptors can be differentiated into four categories according to their function:

High-threshold mechanoreceptors

Also called specific nociceptors, they consist of free nerve endings in the skin that are activated by strong pressure. For example, when the skin is struck, stretched or squeezed.

Nociceptors that respond to intense heat

The latter is the active component of hot chili. These fibers contain VR1 receptors. They are responsible for capturing pain caused by high temperatures (skin burns or inflammation) and itching.

ATP-sensitive nociceptors

ATP is produced by mitochondria, which are a fundamental part of the cell. ATP is the main energy source for cellular metabolic processes. This substance is released when a muscle is injured or when the blood supply is blocked in a certain part of the body (ischemia).

It is also released when there are fast-growing tumors. For this reason, these nociceptors can contribute to pain that occurs in migraines, angina, muscle injuries, or cancer.

Polymodal nociceptors

These respond to intense stimuli such as thermal and mechanical, as well as to chemicals, such as the types mentioned above. They are the most common type of C (slow) fibers.

Cutaneous nociceptors

Cutaneous nociceptors are only activated with intense stimuli, and in the absence of them they are inactive. According to its driving speed and response, two types can be distinguished:

• A- δ nociceptors: they are located in the dermis and epidermis, and respond to mechanical stimulation. Its fibers are covered with myelin, which implies rapid transmission.
• C nociceptors: as mentioned before, they lack myelin and their conduction speed is slower. They are found in the dermis and respond to stimuli of all kinds, as well as to chemical substances secreted after tissue injury.

- Nociceptors of the joints

Joints and ligaments possess high-threshold mechanoreceptors, polymodal nociceptors, and silent nociceptors.

Some of the fibers that contain these receptors possess neuropeptides such as substance P or the peptide associated with the calcitonin gene. When these substances are released there appears to be a development of inflammatory arthritis.

In muscles and joints there are also A- δ and C type nociceptors. The former are activated when there are sustained muscle contractions. While the C respond to heat, pressure and ischemia.

- Visceral nociceptors

The organs of our body have receptors that sense temperature, mechanical pressure, and chemicals contain silent nociceptors. Visceral nociceptors are scattered from one another with several millimeters between them. Although, in some organs, there may be several centimeters between each nociceptor.

All the harmful data captured by the viscera and the skin are transmitted to the central nervous system through different routes.

The vast majority of visceral nociceptors have unmyelinated fibers. Two classes can be distinguished: high-threshold fibers that are only activated by intense noxious stimuli, and nonspecific. The latter can be activated by both harmless and harmful stimuli.

- Silent nociceptors

It is a type of nociceptors that are in the skin and deep tissues. These nociceptors are so named because they are silent or at rest, that is, they do not normally respond to noxious mechanical stimuli.

However, they can "wake up" or begin to respond to mechanical stimulation after injury or during inflammation. This may be due to the fact that the continued stimulation of the injured tissue lowers the threshold for these types of nociceptors, causing them to begin to respond.

When the silent nociceptors are activated, it can induce hyperalgesia (exaggerated perception of pain), central sensitization and allodynia (it consists of feeling pain from a stimulus that does not normally produce it). Most visceral nociceptors are silent.

Ultimately, these nerve endings are the first step that would initiate our perception of pain. They are activated through contact with a harmful stimulus, such as touching a hot object or cutting our skin.

These receptors send information regarding the intensity and location of the painful stimulus to the central nervous system.

Released substances

Pain receptors or nociceptors are activated when a stimulus causes tissue damage or is potentially harmful. For example, when we hit ourselves or feel extreme heat.

Tissue injury causes the release of a wide variety of substances in injured cells, as well as new components that are synthesized at the site of damage.

When these substances are secreted, the nociceptors become sensitized and lower their threshold. This effect is called "peripheral sensitization" and is different from central sensitization, since the latter occurs in the dorsal horn of the spinal cord.

About 15 to 30 seconds after an injury, the area of ​​damage (and several inches around it) turns red. This occurs due to vasodilation, and leads to inflammation. This inflammation reaches its maximum level 5 or 10 minutes after the injury, and is accompanied by hyperalgesia (decreased pain threshold).

Hyperalgesia is a high increase in the sensation of pain in the face of noxious stimuli. This occurs for two reasons: after inflammation, the nociceptors become more sensitive to pain, lowering their threshold.

While, at the same time, silent nociceptors are activated. In the end there is an amplification and increase in the persistence of pain.

The substances released can be:

Protein kinases and globulin

It seems that the release of these substances in damaged tissues causes severe pain. For example, injections under the skin of globulin have been found to cause severe pain.

Arachidonic acid

This is one of the chemicals that are secreted during tissue injuries. It is subsequently metabolized into prostaglandin and cytokines. Prostaglandins increase pain perception and make nociceptors more sensitive to it.

In fact, aspirin eliminates pain by blocking arachidonic acid from turning into prostaglandin.

Histamine

After tissue damage, histamine is released into the surrounding area. This substance stimulates nociceptors and if injected subcutaneously it causes pain.

Nerve growth factor (NGF)

It is a protein that is in the nervous system, essential for neurodevelopment and survival.

When inflammation or injury occurs, this substance is released. NGF indirectly activates nociceptors, causing pain. This has also been observed through subcutaneous injections of this substance.

Calcitonin gene-related peptide (CGRP) and substance P

These substances are also secreted after injury. Inflammation of an injured tissue also leads to the release of these substances, which activate nociceptors. These peptides also cause vasodilation, causing inflammation to spread around the initial damage.

Potassium

A significant correlation has been found between the intensity of pain and a higher concentration of extracellular potassium in the injured area. That is, the greater the amount of potassium in the extracellular fluid, the more pain is perceived.

Serotonin, acetylcholine, low PH and ATP

All these elements are secreted after tissue damage and stimulate nociceptors producing a sensation of pain.

Lactic acid and muscle spasms

When the muscles are hyperactive or when they do not receive the correct blood flow, the concentration of lactic acid increases, causing pain. Subcutaneous injections of this substance excite nociceptors.

Muscle spasms (which lead to the release of lactic acid) can be the result of certain headaches.

Pain from nociceptors to the brain

Nociceptors receive local stimuli and transform them into action potentials. These are transmitted through the primary sensory fibers to the central nervous system.

The fibers of the nociceptors have their cell bodies in the dorsal (posterior) root ganglia.

The axons that are part of this area are called afferents because they carry nerve impulses from the periphery of the body to the central nervous system (spinal cord and brain).

These fibers reach the spinal cord through the dorsal root ganglia. Once there, they continue to the gray matter of the posterior horn of the medulla.

The gray substance has 10 different sheets or layers, and different fibers arrive at each sheet. For example, the A-δ fibers of the skin terminate in laminae I and V; while C fibers reach lamina II, and sometimes I and III.

Most nociceptive neurons in the spinal cord make connections to supraspinal, bulbar, and thalamic centers in the brain.

Once there, the pain messages reach other higher areas of the brain. Pain has two components, one sensory or discriminative and the other affective or emotional.

The sensory element is captured by the connections of the thalamus with the primary and secondary somatosensory cortex. In turn, these areas send information to the visual, auditory, learning and memory areas.

While, in the affective component, the information travels from the medial thalamus to areas of the cortex. Specifically prefrontal areas such as the supraorbital frontal cortex.

References

1. Carlson, NR (2006). Physiology of behavior 8th Ed. Madrid: Pearson.
2. Dafny, N. (nd). Chapter 6: Pain Principles. Retrieved on March 24, 2017, from Neuroscience online (The University of Texas Health Science Center at Houston): nba.uth.tmc.edu.
3. Dubin, AE, & Patapoutian, A. (2010). Nociceptors: the sensors of the pain pathway. The Journal of Clinical Investigation, 120 (11), 3760–3772.
4. FERRANDIZ MACH, M. (sf). PATHOPHYSIOLOGY OF PAIN. Retrieved on March 24, 2017, from Hospital de la Santa Creu i Sant Pau. Barcelona: scartd.org.
5. Meßlinger, K. (1997). Was ist ein Nozizeptor? Anaesthesist. 46 (2): 142-153.
6. Nociceptor. (sf). Retrieved on March 24, 2017, from Wikipedia: en.wikipedia.org.