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Chapter 6: Pain Principles

Nachum Dafny, Ph.D., Department of Neurobiology and Anatomy, The UT Medical School at Houston

Reviewed and revised 07 Oct 2020

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Figure 6.1 Three pathways carrying pain sensation from the periphery to the central nervous system.

Most of the sensory and somatosensory modalities are primarily informative, whereas pain is a protective modality. Pain differs from the classical senses (hearing, smell, taste, touch, and vision) because it is both a discriminative sensation and a graded emotional experience associated with actual or potential tissue damage.

Pain is a submodality of somatic sensation. The word "pain" is used to describe a wide range of unpleasant sensory and emotional experiences associated with actual or potential tissue damage. Nature has made sure that pain is a signal we cannot ignore. Pain information is transmitted to the CNS via three major pathways (Figure 6.1).

Most ailments of the body cause pain. The ability to diagnose different diseases depends to a great extent on the knowledge of the different qualities and causes of pain. Sensitivity and reactivity to noxious stimuli are essential to the well-being and survival of an organism. Pain travels through redundant pathways, ensuring to inform the subject: “Get out of this situation immediately.” Without these attributes, the organism has no means to prevent or minimize tissue injury. Individuals congenitally insensitive to pain are easily injured and most of them die at an early age.

For thousands of years, physicians have tried to treat pain without knowing the details of the ways in which pain is signaled from the injured part of the body to the brain, or the ways in which any of their remedies worked. Recent discoveries about how the body detects, transmits and reacts to painful stimuli, have allowed physicians to relieve both acute and chronic pain.

6.1 Pain Receptors

Pain is termed nociceptive (nocer – to injure or to hurt in Latin), and nociceptive means sensitive to noxious stimuli. Noxious stimuli are stimuli that elicit tissue damage and activate nociceptors.

Nociceptors are sensory receptors that detect signals from damaged tissue or the threat of damage and indirectly also respond to chemicals released from the damaged tissue. Nociceptors are free (bare) nerve endings found in the skin (Figure 6.2), muscle, joints, bone and viscera. Recently, it was found that nerve endings contain transient receptor potential (TRP) channels that sense and detect damage. The TRP channels are similar to voltage-gated potassium channels or nucleotide-gated channels, having 6 transmembrane domains with a pore between domains 5 and 6. They transduce a variety of noxious stimuli into receptor potentials, which in turn initiate action potential in the pain nerve fibers. This action potential is transmitted to the spinal cord and makes a synaptic connection in lamina I and/or II. The cell bodies of nociceptors are mainly in the dorsal root and trigeminal ganglia. No nociceptors are found inside the CNS.

Figure 6.2 Different nociceptors/free nerve endings, and the fibers carrying pain sensation from the nociceptors to the spinal cord.

Nociceptors are not uniformly sensitive. They fall into several categories, depending on their responses to mechanical, thermal, and/or chemical stimulation liberated by the damage, tumor, and/or inflammation.

Skin Nociceptors. Skin nociceptors may be divided into four categories based on function. The first type is termed high threshold mechanonociceptors or specific nociceptors. These nociceptors respond only to intense mechanical stimulation such as pinching, cutting or stretching. The second type is the thermal nociceptors, which respond to the above stimuli as well as to thermal stimuli. The third type is chemical nociceptors, which respond only to chemical substances (Figure 6.2). A fourth type is known as polymodal nociceptors, which respond to high intensity stimuli such as mechanical, thermal and to chemical substances like the previous three types. A characteristic feature of nociceptors is their tendency to be sensitized by prolonged stimulation, making them respond to other sensations as well.

Joint Nociceptors. The joint capsules and ligaments contain high-threshold mechanoreceptors, polymodal nociceptors, and "silent" nociceptors. Many of the fibers innervating these endings in the joint capsule contain neuropeptides, such as substance P (SP) and calcitonin gene-related peptide (CGRP). Liberation of such peptides is believed to play a role in the development of inflammatory arthritis.

Visceral Nociceptors. Visceral organs contain mechanical pressure, temperature, chemical and silent nociceptors. The visceral nociceptors are scattered, with several millimeters between them, and in some organs, there are several centimeters between each nociceptor (Figure 6.3). Many of the visceral nociceptors are silent. The noxious information from visceral organs and skin are carried to the CNS in different pathways (Figures 6.3 and 6.4).

Figure 6.3 Visceral nociceptors and the fibers and pathways carrying the noxious information to the CNS.

Figure 6.4

 

Silent Nociceptors. In the skin and deep tissues there are additional nociceptors called "silent" or "sleep" nociceptors. These receptors are normally unresponsive to noxious mechanical stimulation, but become “awakened” (responsive) to mechanical stimulation during inflammation and after tissue injury. One possible explanation of the "awakening" phenomenon is that continuous stimulation from the damaged tissue reduces the threshold of these nociceptors and causes them to begin to respond. This activation of silent nociceptors may contribute to the induction of hyperalgesia, central sensitization, and allodynia (see below). Many visceral nociceptors are silent nociceptors.

Activation of the nociceptor initiates the process by which pain is experienced, (e.g., we touch a hot stove or sustain a cut). These receptors relay information to the CNS about the intensity and location of the painful stimulus.

6.2 Factors that Activate Nociceptors

Nociceptors respond when a stimulus causes tissue damage, such as that resulting from cut strong mechanical pressure, extreme heat, etc. The damage of tissue results in a release of a variety of substances from lysed cells as well as from new substances synthesized at the site of the injury (Figure 6.5). Some of these substances activate the TRP channels which in turn initiate action potentials. These substances include:

1. Globulin and protein kinases. It has been suggested that damaged tissue releases globulin and protein kinases, which are believed to be amongst the most active pain-producing substances. Minute subcutaneous injections of globulin induce severe pain.
   
2. Arachidonic acid. Arachidonic acid is one of the chemicals released during tissue damage. It is then metabolized into prostaglandin (and cytokines). The action of the prostaglandins is mediated through a G protein, protein kinase A cascade. The prostaglandins block the potassium efflux released from nociceptors following damage, which results in additional depolarization. This makes the nociceptors more sensitive. Aspirin is an effective pain killer because it blocks the conversion of arachidonic acid to prostaglandin.
   
3. Histamine. Tissue damage stimulates the mast cells to release histamine to the surrounding area. Histamine excites the nociceptors. Minute subcutaneous injections of histamine elicit pain.
   
4. Nerve growth factor (NGF). Inflammation or tissue damage triggers the release of NGF. NGF then binds to TrkA receptors on the surfaces of nociceptors leading to their activation. Minute subcutaneous injections of NGF elicit pain.
   
5. Substance P (SP) and calcitonin gene-related peptide (CGRP) are released by injury. Inflammation of tissue damage also results in SP and CGRP release, which excites nociceptors. Minute subcutaneous injection of substance P and CGRP elicits pain. Both peptides produce vasodilation, which results in the spread of edema around the initial damage.
   
6. Potassium - K⁺. Most tissue damage results in an increase in extracellular K⁺. There is a good correlation between pain intensity and local K⁺ concentration.
   
7. Serotonin (5-HT), acetylcholine (ACh), low pH (acidic) solution, and ATP. These substances are released with tissue damage. Subcutaneous injections of minute qualities of these products excite nociceptors.
   
8. Muscle spasm and lactic acid. Not only can some headaches result from muscle spasms of smooth muscle, stretching of a ligament can also elicit pain. When muscles are hyperactive or when blood flow to a muscle is blocked, lactic acid concentration increases and pain is induced. The greater the rate of tissue metabolism, the more rapidly the pain appears. Minute subcutaneous injections of lactic acid excite nociceptors.

Figure 6.5 Tissue damage and the variety of the substances released from the injury site that activate the nociceptors.

The release of these substances sensitizes the nociceptors (C fibers) and reduces their threshold. This effect is referred to as peripheral sensitization (in contrast to central sensitization that occurs in the dorsal horn).

Figure 6.6 This shows the development of the flare and the area that becomes hyperalgesic as a result of injury.

Within 15-30 seconds after injury, an area of several cm around the injured site shows reddening (caused by vasodilation) called a flare. This response (inflammation) becomes maximal after 5-10 minutes (Figure 6.6), and this region shows a lowered pain threshold (i.e., hyperalgesia).

Hyperalgesia. Hyperalgesia is an increased painful sensation in response to additional noxious stimuli. One explanation for hyperalgesia is that the threshold for pain in the area surrounding an inflamed or injured site is lowered. An additional explanation is that the inflammation activates silent nociceptors and/or the damage elicits ongoing nerve signals (prolong stimulation), which led to long-term changes and sensitized nociceptors. These changes contribute to an amplification of pain or hyperalgesia, as well as an increased persistence of the pain. If one pricks normal skin with a sharp probe, it will elicit sharp pain followed by reddened skin. The reddened skin is an area of hyperalgesia.

Allodynia. Allodynia is pain resulting from a stimulus that does not normally produce pain. For example, light touch to sunburned skin produces pain because nociceptors in the skin have been sensitized as a result of reducing the threshold of the silent nociceptors. Another explanation of allodynia is that when peripheral neurons are damaged, structural changes occur and the damaged neurons reroute and make connection also to sensory receptors (i.e., touch-sensitive fibers reroute and make synaptic connection into areas of the spinal cord that receive input from nociceptors).

In conclusion, the several kinds of endogenous chemicals are produced with tissue damage and inflammation. These products have excitatory effects on nociceptors. However, it is not known whether nociceptors respond directly to the noxious stimulus or indirectly by means of one or more chemical intermediaries released from the traumatized tissue.

6.3 Pain Thresholds and Just Noticeable Differences

Exposing the skin to controlled heat (produced by heating element or laser) makes it possible to measure the threshold for pain. When the temperature of the skin reaches 45 ± 1°C, subjects report pain. Non-noxious thermal (< 45°C) receptors are innervated by different types of nerve fibers than those responding to the pain. A temperature of approximately 45ºC denatures tissue protein and elicits damage in all subjects (Figure 6.7). That is, the pain threshold in all subjects is about the same. However, the response to pain is different among people.

Figure 6.7 Distribution curve obtained from experimental testing of the thermal pain threshold of many male and female subjects.

Pain is measured by the degree of pain intensity. Different degrees of pain intensity are defined as Just Noticeable Differences (JND). There are 22 JND for pain elicited by heat to the skin (Figure 6.8A). This discrimination is possible because the discharge frequency of the nociceptors increases with increasing skin temperature (Figure 6.8B). Thus, nociceptors also supply information on the stimulus intensity (intensity coding) in addition to the injury location.

Figure 6.8A		Figure 6.8B
Expression of pain intensity in just noticeable differences (JNDs) at different intensities of stimulus (A). Response of single nocineurons to incremental temperature intensity (B).

6.4 Pain Fibers

The cell bodies of the primary afferent pain neurons from the body, face, and head are located in the dorsal root ganglia (DRG) and in the trigeminal ganglia respectively. Some of these cell bodies give rise to myelinated axons (A delta fibers), and others give rise to unmyelinated axons (C fibers). The free nerve endings arise from both A delta fibers and the unmyelinated C fibers, which are scattered together (Figure 6.9).

Figure 6.9 Conduction of noxious information via A delta and C fibers.

A delta fibers (group III fibers) are 2-5 mm in diameter, myelinated, have a fast conduction velocity (5-40 meters/sec), and carry information mainly from the nociceptive-mechanical or mechanothermal-specific nociceptors. Their receptive fields are small. Therefore, they provide precise localization of pain.
C fibers (group IV fibers) are 0.4-1.2 mm in diameter, unmyelinated, have a slow conduction velocity (0.5-2.0 meters/sec), and are activated by a variety of high-intensity mechanical, chemical and thermal stimulation and carry information from polymodal nociceptors. C-fibers comprise about 70% of all the fibers carrying noxious input. Two classes of C-fibers have been identified. The receptive field of these neurons is large and, therefore, less precise for pain localization.
Upon entering the spinal cord, the pain fibers bifurcate and ascend and descend to several segments, forming part of the tract of Lissauer before synapsing on neurons on Rexed layers I to II. In general, nociceptors responding to noxious stimuli transmit the information to the CNS via A delta fibers, which make synaptic connections to neurons in Rexed layer I (nucleus posterior marginalis). The nociceptors responding to chemical or thermal stimuli (i.e., the polymodal nociceptors) carry their activity mainly by C unmyelinated fibers. One class of C fibers terminates in Rexed layer I, and the second class terminates in Rexed layer II (substantia gelatinosa). These fibers release substance P, glutamate, aspartate calcitonin gene related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and nitric oxide.

6.5 Double Pain Sensations

Two sequential pain sensations in short time intervals is the result of sudden painful stimulation. The first one is immediately after the damage. It is followed several seconds later with additional pain sensation. These two separate sensations are several seconds apart because a fast transmitting information sensation is carried via A delta fibers and is followed several seconds later with slow transmitting pain information carried via C fibers. This phenomenon is known as “double pain sensation” (Figure 6.9).

Two experimental procedures were used to verify which information is carried by which fibers.

1. Externally applied pressure, such as compression of the skin above a nerve, first blocks the myelinated A delta fibers, while C fibers continue to conduct action potentials and allow the slow conducting pain to be carried.
   
2. A low dose of local anesthesia applied to peripheral nerves blocks the unmyelinated C fibers before the myelinated A delta fibers. Under this condition, the slow conducting pain information is blocked, and only the fast conducting pain information by A delta fibers is carried to the CNS. This experiment provides additional evidence that two different types of nerve fibers carry noxious information.

6.6 Nociceptive Neurons in the Spinal Cord (Nocineurons)

The synaptic terminals of the axons of the dorsal root ganglion, which carry noxious information arriving to Rexed layers I and II (Figure 6.10), release neurochemical agents such as substance P (SP), glutamate, aspartate, vasoactive intestinal peptide (VIP), cholecystokinin (CCK), somatostatin, calcitonin gene-related peptide (CGRP), galanin, and other agents. These agents activate the nocineurons. It was shown that when SP and CGRP are applied locally within the spinal cord dorsal horn, glutamate is released. The release of glutamate excites the nocineurons. Furthermore, SP receptors (neurokinin receptors) and NMDA receptors (glutamate) interact which result that the NMDA receptors will become more sensitive to glutamate, which results in central sensitization. The functions of these peptides are largely unknown but they presumably mediate slow, modulatory synaptic actions in the dorsal horn neurons. The neuropeptides are always co-localized with other "classical" neurotransmitters.

There are four general types of nocineurons in the spinal cord (Figure 6.10):

1. High threshold mechanoreceptor neurons or nociceptive specific neurons. These neurons are excited only by noxious cutaneous and/or visceral stimuli. The nociceptive afferent fibers release glutamate and different neuropeptides to activate the dorsal horn neurons.
   
2. Chemical nociceptor neurons are excited by chemical or thermal noxious stimulus in the skin or in visceral organs.
   
3. Thermal nociceptor neurons are excited by chemical or thermal noxious stimulus in the skin or in visceral organs.
   
4. Polymodal-nociceptive neurons or multi, or wide dynamic range nociceptive neurons. These neurons are excited by both noxious and non-noxious cutaneous and/or visceral stimuli (polymodal nociceptive neurons). These neurons are activated by a variety of noxious stimuli (mechanical, thermal, chemical, etc.) and respond incrementally to increasing intensity of the stimuli.

Figure 6.10 Four different nocineurons in the spinal cord.

Rexed lamina I contains a higher proportion of nociceptive specific neurons, whereas Rexed lamina II contains predominantly multi-receptive wide dynamic range neurons. The nociceptive-specific neurons alert the subject when a stimulus is noxious, and the multi-receptive neurons provide the subject with information about the parameters of the noxious stimulus. In general, C fibers release neuropeptides such as substance P whereas the A delta fibers release glutamate.

6.7 Classification of Pain

Pain has been classified into three major types:

1. Pricking pain. Pain caused by a needle, pin prick, skin cut, etc. - elicits a sharp, pricking quality, stinging pain sensation carried fast by the A delta fibers. The pain is precisely localized and of short duration. Pricking pain is also called fast pain, first pain or sensory pain. Pricking pain is present in all individuals and is a useful and necessary component of our sensory repertoire. Without this type of protective pain sensation, everyday life would be difficult. Pricking pain arises mainly from the skin, and carried mainly by A delta fibers which permits discrimination (i.e., permits the subject to localize the pain).
   
2. Burning pain or soreness pain. Pain caused by inflammation, burned skin, etc., is carried by the C fibers (slowly conducted pain nerve fibers). This type of pain is a more diffuse, slower to onset, and longer in duration. It is an annoying pain and intolerable pain, which is not distinctly localized. Like pricking pain, burning pain arises mainly from the skin. It is carried by the paleospinothalamic tract. (The old primitive transmission system for diffuse pain which does not permit exact localization.)
   
3. Aching pain is a sore pain. This pain arises mainly from the viscera and somatic deep structures. Aching pain is not distinctly localized and is an annoying and intolerable pain. Aching pain is carried by the C fibers from the deep structures to the spinal cord.
   

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