6. Pain Principles
Part 2 of 3

Nachum Dafny, Ph.D.
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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.

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).

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.

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 denaturates 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.

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.

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).

1. 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.
2. 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.

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