Pain Physiology: Pain Processes, Transduction, Sensory Aspects, Physiological Processes and Monitoring Methods

It is a subjective experience with two complementary aspects.

An aspect is a localized sensation in a particular part of the body; the other is an unpleasant quality of varying severity commonly associated with behaviors aimed at alleviating or ending the experience.

Pain has a lot in common with other sensory modalities. First, there are specific pain receptors. These are nerve endings, present in most tissues in the body, that only respond to harmful or potentially harmful stimuli.

Second, the messages initiated by these noxious stimuli are transmitted by specific and identified nerves to the spinal cord .

The sensitive nerve ending in tissue and the nerve attached to it form a unit called primary afferent nociceptors . The primary afferent nociceptor contacts second-order pain-transmitting neurons in the spinal cord.

Second-order cells carry the message through well-defined pathways to higher centers, including the reticular formation of the brainstem, the thalamus, the somatosensory cortex, and the limbic system . The processes underlying pain perception are believed to primarily involve the thalamus and cortex.

Research on the basic mechanisms underlying pain is an increasingly exciting and promising area.

However, most of what is known about the anatomy and physiology of pain comes from studies of experimentally induced cutaneous (skin) pain, while the majority of clinical pain arises from deep tissues.

Therefore, although experimental studies provide fairly good models for acute pain, they are poor models for clinical chronic pain syndromes.

Not only do they provide little information about the muscles, joints, and tendons most often affected by chronically painful conditions, they fail to address the wide range of psychosocial factors that profoundly influence the experience of pain.

To improve our understanding and treatment of pain, we will need better animal models of human pain and better tools for studying clinical pain.

Pain processes

There are four main processes: transduction, transmission, modulation, and perception. Transduction refers to the processes by which tissue-damaging stimuli activate nerve endings.

Transmission refers to the relay functions by means of which the message is transmitted from the site of tissue injury to the brain regions underlying perception.

Modulation is a recently discovered neural process that acts specifically to reduce activity in the transmission system.

Perception is the subjective awareness produced by sensory signals; it involves the integration of many sensory messages into a coherent and meaningful whole. Perception is a complex function of various processes, including attention, expectations, and interpretation.

Transduction, transmission, and modulation are neural processes that can be studied objectively using methods that involve direct observation.

In contrast, although there is an indisputable neural basis for it, pain awareness is a perception and therefore subjective, so it cannot be directly and objectively measured.

Even if we could measure the activity of pain-transmitting neurons in another person, to conclude that that person is in pain would require an inference based on indirect evidence.

Transduction

Three types of stimuli can activate pain receptors in peripheral tissues: mechanical (pressure, pinch), heat, and chemical. Mechanical and heat stimuli are usually brief, while chemical stimuli are usually long-lasting.

Nothing is known about how these stimuli activate nociceptors. Nociceptive nerve endings are so small and scattered that they are difficult to find, let alone study.

However, some studies have been conducted on the effects of chemicals on the firing rate of identified primary afferent nociceptors. A variety of pain-producing chemicals activate or sensitize primary afferent nociceptors.

Some of them, such as potassium, histamine, and serotonin, can be released by cells in damaged tissues or by circulating blood cells that migrate from blood vessels to the area of ​​tissue damage.

Other chemicals, such as bradykinin, prostaglandins, and leukotrienes, are synthesized by enzymes activated by tissue damage. All of these pain-causing chemicals are found in increasing concentrations in regions of inflammation and pain.

Obviously, the transduction process involves a large number of chemical processes that probably work together to activate the primary afferent nociceptor.

In theory, any of these substances could be measured to provide an estimate of the peripheral stimulus for pain. In practice, such trials are not available to physicians.

It should be noted that most of our knowledge of primary afferent nociceptors is derived from studies of the cutaneous nerves.

Although this work is of general importance, most of the clinically significant pain is generated by processes in the musculoskeletal or deep visceral tissues.

Scientists are beginning to study the stimuli that activate nociceptors in these deep tissues. In muscle, there are primary afferent nociceptors that respond to pressure, muscle contraction, and irritating chemicals.

Muscle contraction under ischemic conditions is an especially powerful stimulus for some of these nociceptors.

Despite advances in our understanding of the physiology of musculoskeletal nociceptors, we still know very little about the mechanisms underlying common clinical problems, such as low back pain.

Even when there is degeneration of the spine and compression of a nerve root, a condition generally recognized as extremely painful, we do not know which nociceptors are activated or how they are activated. We also do not know what the process that leads to pain is about.

Transmission

Peripheral nervous system

The nociceptive message is transmitted from the periphery to the central nervous system by the axon of the primary afferent nociceptor.

This neuron has its cell body in the dorsal root ganglion and a long process, the axon, that divides and sends a branch to the periphery and another to the spinal cord. The axons of the primary afferent nociceptors are relatively thin and conduct impulses slowly.

Pathways of pain in the central nervous system

Primary afferent nociceptors transmit impulses to the spinal cord (or if they arise from the head, to the brainstem medulla).

In the spinal cord, primary afferent nociceptors terminate near second-order nerve cells in the dorsal horn of gray matter. Primary afferent nociceptors release chemical transmitters from their spinal terminals.

These transmitters activate second-order pain transmission cells. The identity of these transmitters has not been established, but candidates include small polypeptides such as substance P and somatostatin, as well as amino acids such as glutamic or aspartic acid.

The axons of some of these second-order cells cross to the opposite side of the spinal cord and project long distances to the brainstem and thalamus. The route for pain transmission is in the anterolateral quadrant of the spinal cord.

Most of our information on the anatomy and physiology of pain transmission pathways in the central nervous system is derived from animal studies.

However, it is known that in humans, lesions of this anterolateral pathway permanently impair the sensation of pain and that electrical stimulation of the same causes pain.

There are two main targets for ascending nociceptive axons in the anterolateral quadrant of the spinal cord: the thalamus and the medial reticular formation of the brainstem.

Our knowledge is most extensive for spinal cells whose axons project directly into the thalamus, that is, the cells of the spinothalamic tract.

The spinothalamic pathway is involved in the perception of human pain because injuries to it, at any level, produce lasting alterations in the sensation of pain.

The other main ascending nociceptive pathway in the anterolateral quadrant is the spinoreticular tract. The medullary reticular formation receives a large direct projection from the spinal cord, as well as from the branches of some of the spinal neurons that project into the thalamus.

Sensory versus affective aspects of pain

The processes set in motion by noxious stimuli can be divided into two broad categories. On the one hand, there are the sensory processes that lead to the detection and identification of the stimulus.

On the other hand, presumably due to the tissue-damaging potential of the noxious stimulus, aversive behavioral sequelae, such as withdrawal and escape, can terminate the stimulus and protect the body. In relation to these two categories of response, there are two subjective aspects of pain: sensory and affective.

The sensory aspects refer to the detection, location, evaluation of the intensity and identification of the stimulus. Focusing on the sensory aspects, a person may describe their pain as a mild burning pain located on the back of the hand.

In contrast, the affective or unpleasant aspect of pain correlates with the aversive drive to terminate the noxious stimulus and is described by terms that are not specifically linked to a sensory experience, eg, persistent, uncomfortable, or unbearable.

The affective aspects would also be accompanied by changes in mood, such as anxiety and depression, which are generally considered psychological rather than sensory.

The difference between the sensory and affective aspects of pain can be further illustrated by the distinction between pain threshold and pain tolerance.

For example, if one delivers calibrated thermal stimuli to the skin, most people will report that the sensation becomes painful in a narrow range of skin temperatures (43-46ºC). The temperature that is called painful 50 percent of the time would be pain detection or sensory threshold.

Modulation

The aforementioned processes were discussed in terms of a highly reliable pain transmission system, assuming that pain intensity is a direct function of nociceptive activity.

Indeed, the excellent correlation between stimulus intensity, impulses in primary afferent nociceptors, and reported pain intensity demonstrated in human subjects under experimental conditions often does not apply to the clinical situation.

The most notable observations are those in which patients subjected to injuries that should be very painful do not report significant pain.

A hypothesis for spontaneous analgesia arose when it was discovered that electrical stimulation of certain brain regions blocks responses to noxious stimulation in laboratory animals.

The failure of the pain suppression system has been suggested to represent certain types of chronic pain states, but most pain experts consider this conclusion premature. Much more work is needed to determine the extent to which this pain modulating network operates on chronic pain.

Physiological processes that improve pain and can lead to chronicity

One of the problems for patients, physicians, and disability examiners is how to explain pain experiences that seem disproportionate to objectively verifiable physical findings or illness or injury.

Although it is well known and accepted that various psychosocial factors can potentiate pain, the role of various physiological processes in the amplification and maintenance of pain may not be adequately considered when evaluating patient complaints.

Sensitization

Tissue damage initiates a variety of processes that sustain and amplify pain. With repeated stimuli, the thresholds of the primary afferent nociceptors progressively decrease, so that normally innocuous stimuli become painful.

For some primary afferent nociceptors, repeated noxious stimuli can induce continuous activity that lasts for several hours. The most familiar example of this is sunburn, in which the skin becomes a source of pain.

Hot water applied to the skin is perceived as excruciatingly painful and a friendly pat on the back is excruciating. Other examples are the sensitivity of a sprained ankle or an arthritic joint.

In these situations, it is painful to bear weight or even move the affected joint. Sensitization is an important feature of many and perhaps most clinically significant pain, but its cellular mechanism is unknown.

Sympathetic Nervous System Hyperactivity

Patients with relatively minor injuries occasionally develop pain disproportionate to their injuries. Such pain often becomes progressively worse rather than following the usual course of decline over time.

Importantly, the pain persists well beyond the time the original tissue-damaging process has ended. In addition, the location of the pain can be quite different from the site of the precipitating pathology.

In some of these patients, sympathetic nervous system overactivity clearly plays an important role in pain maintenance because selective blockage of the sympathetic outlet produces immediate and dramatic relief.

The pain is usually accompanied by signs of sympathetic hyperactivity, such as a cold sweaty limb (vasoconstrictor). In addition, the skin may be hypersensitive to the touch, as if the nociceptors were sensitized.

Over time, osteoporosis, arthritis, and muscle atrophy can develop and permanent impairment of function can occur. This condition, called reflex sympathetic dystrophy, usually responds to sympathetic blocks and physical therapy.

Physiological studies in animals indicate that sympathetic outflow can induce the discharge of primary afferent nociceptors. This is most prominent in damaged and regenerative afferents, but also occurs in sensitized undamaged afferents.

Reflex sympathetic dystrophy syndrome is relatively rare in its full form, but sympathetic activity could be a common factor in maintaining or amplifying pain that would normally fade as injured tissues heal.

If this were at ease, local signs of increased sympathetic activity could help provide objective evidence that a pain-producing disease process is present.

Muscle contraction

Nociceptor activity produces a sustained contraction in the muscles. In the extremities, this muscle contraction produces flexion, a primitive form of retraction that is presumably a protective movement.

Disease in the abdominal viscera (eg, intestine, liver) causes tension in the muscles of the abdominal wall. Pain arising from musculoskeletal structures also causes contraction and tenderness in other muscles innervated by the same spinal segment.

There is some evidence that this disseminated muscle contraction plays an important role in clinically significant pain. In patients with persistent pain it is common to find small areas in the muscles that are quite tender.

Pressure on these myofascial trigger points can reproduce the patient’s pain, and locally anesthetizing the points (or other manipulations of the points) can relieve days or months.

The physiological basis for these trigger points is unknown, but clinical evidence suggests that they are often involved in pain maintenance in the absence of ongoing tissue damage.

Self-Sufficient Pain Processes: Livingston’s “Vicious Circle”

From the material just discussed, clinical observations clearly indicate that various processes are set in motion by stimuli that damage tissues and activate nociceptors.

In peripheral tissues, pain-producing substances are released that sensitize nociceptors so that normally innocuous stimuli can activate them.

In addition, the nociceptors themselves release factors such as substance P which in turn cause vasodilation, edema, and the release of sensitizing substances from non-neural cells.

Presumably, these processes play a role in activating the host’s defenses against infection or toxins. However, they do prolong and amplify pain.

Neuropathic pain

Damage to the peripheral or central nervous systems can lead to chronic pain. For example, in some diseases that affect the peripheral nerves, such as diabetes mellitus or alcohol toxicity, pain is very common.

Traumatic peripheral nerve injury is rarely painful, but when it is, it can be dramatic. Causalgia (heat pain) is an example of pain induced by a traumatic injury to a peripheral nerve.

Causalgia is a syndrome characterized by severe pain and signs of hyperactivity of the sympathetic nervous system. Similarly, central nervous system injuries are rarely painful, but when they are, the pain is severe and resistant to treatment.

There are certain characteristics of neuropathic pain. It often begins several days or weeks after the injury that causes it and tends to get worse before stabilizing.

It is usually accompanied by sensory abnormalities, including, paradoxically, deficits in pain sensation and painful hyperresponsiveness to ordinarily innocuous stimuli.

The mechanisms of neuropathic pain are not fully understood, but there are several factors that could contribute to them (Ochoa, 1982).

Damaged primary afferents, which presumably include nociceptors, acquire certain properties when they begin to regenerate. These include spontaneous activity, mechanical sensitivity, and sensitivity to sympathetic nervous system activity.

Acute pain versus chronic pain

Is there a physiological basis for differentiating between acute and chronic pain? Little is known about the effects of prolonged pain on the central nervous system.

There is some evidence that the transition from acute pain to chronic pain alters the neurophysiology of patients in a way that makes them somewhat different from those with acute pain.

In arthritic rats, for example, there are changes in the peripheral nerves that alter their range of response to applied stimuli, and there may also be changes in the central pathways for pain transmission.

Experiments with rats in which nerves have been damaged and observed over time have shown changes in the central nervous system, but it is not known how these changes are related to pain.

People with recurring headaches, arthritis, low back pain, angina, or low-grade malignancies may have had pain for years. Complaints, treatment, and patient reactions may be different for each of these conditions.

In some cases, psychological factors are important. These factors are particularly important in patients with low back pain, facial pain, and headaches, and appear to be more prominent the longer the pain persists.

Psychological and somatic factors are not completely separated to maintain pain. For example, stress and anxiety increase both muscle contraction and sympathetic output and are expected to exacerbate any ongoing pain problems to which they contribute.

Conversely, any treatment that induces relaxation will reduce these factors and decrease pain. This may be an important connection between psychosocial and somatic factors that influence pain tolerance.

Possible Physiological Monitoring Methods

In this chapter, we have briefly reviewed the anatomy, physiology, and pharmacology of nociceptive transduction, transmission, and modulation. These are objective and potentially observable phenomena initiated by stimuli that damage or threaten tissue.

As we learn more about the transduction process, it may be feasible to measure the concentration of substances in regions of ongoing tissue damage that activate or sensitize primary afferent nociceptors.

This could give an estimate of the level of stimulation of chemically sensitive nociceptors. The most promising technique at present is the direct recording of electrical activity in primary afferents. This is technically possible and has been used in research, but is not currently available for general clinical use.

Monitoring the central pathways of pain transmission is not practical with available technology. Although theoretically possible, registering individual units within the human nervous system requires a potentially dangerous surgical procedure.

Evoked potential or multiple unit studies do not have the required specificity or spatial resolution to allow the collection of meaningful data on clinical pain. Technically it is possible to measure the chemicals released at spinal synapses by primary afferent nociceptors.

If the concentration of such chemicals in cerebrospinal fluid could be correlated with the activity of primary afferent nociceptors or with the severity of clinical pain, this could provide evidence similar to that derived from recording the activity of primary afferents.

However, at this time, the transmitter (s) for the primary afferent nociceptors are unknown.

Another approach is to use positron emission tomography (PET) to monitor metabolic activity in central nervous system pain pathways.

Positron emission tomography is a noninvasive scanning technique that can provide evidence of focal brain activity and the concentration of certain chemicals.

This technique requires that enough neurons are active in a large enough region for a long enough period of time to be detected. Due to the topographic organization of the cortex, this technique could be used to control the somatosensory cortex.

An accurate map of the body’s surface extends many millimeters from the crust. The representation of the face and the hand in this map is very large, so it is possible to detect the continuous activity produced by the nociceptive entry of these regions.

At present, there is no evidence that such measures show anything in chronic pain patients.

Indirect measurements, such as those of sympathetic nervous system activity (skin temperature or skin resistance) or muscle contraction in painful areas may be helpful in providing objective evidence of sustained nociceptive delivery.

The measurement of skin temperature over large areas of the body’s surface, thermography, is being used clinically, but is not yet widely accepted as a reliable indicator of pain.

Although they are simple, painless, and safe indicators of sympathetic function, indirect measures of pain delivery such as thermography can be misleading.

Sympathetic changes can be produced by nonspecific factors such as surprise or anxiety that do not involve pain.

On the other hand, if changes in sympathetic activity are highly localized, persistent, and consistent with the reported location of the patient’s pain, routine assessment of sympathetic function with techniques such as thermography in patients with chronic pain could provide clues to the mechanisms. that hold the pain.

Ultimately, the presence of pain in another individual is always inferred. Even if we could measure pain directly, such a measure would not be adequate to describe the experience of pain, and it is the experience that affects functioning, including the ability to work.