The task of medicine is to preserve and restore health and to relieve suffering. Understanding pain is essential to both of these goals. Because pain is universally understood as a signal of disease, it is the most common symptom that brings a patient to a physician's attention. The function of the pain sensory system is to protect the body and maintain homeostasis. It does this by detecting, localizing, and identifying potential or actual tissue-damaging processes. Because different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient's pain complaint provide important diagnostic clues. It is the physician's responsibility to provide rapid and effective pain relief.
Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These properties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present.
The Primary Afferent Nociceptor
A peripheral nerve consists of the axons of three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons (Fig. 11-1). The cell bodies of primary sensory afferents are located in the dorsal root ganglia in the vertebral foramina. The primary afferent axon has two branches: one projects centrally into the spinal cord and the other projects peripherally to innervate tissues. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter afferent fibers, A-beta (Aβ), respond maximally to light touch and/or moving stimuli; they are present primarily in nerves that innervate the skin. In normal individuals, the activity of these fibers does not produce pain. There are two other classes of primary afferents: the small-diameter myelinated A-delta (Aδ) and the unmyelinated (C fiber) axons (Fig. 11-1). These fibers are present in nerves to the skin and to deep somatic and visceral structures. Some tissues, such as the cornea, are innervated only by Aδ and C fiber afferents. Most Aδ and C fiber afferents respond maximally only to intense (painful) stimuli and produce the subjective experience of pain when they are electrically stimulated; this defines them as primary afferent nociceptors (pain receptors). The ability to detect painful stimuli is completely abolished when conduction in Aδ and C fiber axons is blocked.
Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary afferents with cell bodies in the dorsal root ganglion, and sympathetic postganglionic fibers with cell bodies in the sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ), small-diameter myelinated (Aδ), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.
Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond to heat; intense cold; intense mechanical stimuli, such as a pinch; changes in pH, particularly an acidic environment; and application of chemical irritants including adenosine triphosphate (ATP), serotonin, bradykinin, and histamine.
When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered, and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators such as bradykinin, nerve-growth factor, some prostaglandins, and leukotrienes contribute to this process, which is called sensitization. Sensitization occurs at the level of the peripheral nerve terminal (peripheral sensitization) as well as at the level of the dorsal horn of the spinal cord (central sensitization). Peripheral sensitization occurs in damaged or inflamed tissues, when inflammatory mediators activate intracellular signal transduction in nociceptors, prompting an increase in the production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. These changes increase the excitability of nociceptor terminals and lower their threshold for activation by mechanical, thermal, and chemical stimuli. Central sensitization occurs when activity, generated by nociceptors during inflammation, enhances the excitability of nerve cells in the dorsal horn of the spinal cord. Following injury and resultant sensitization, normally innocuous stimuli can produce pain. Sensitization is a clinically important process that contributes to tenderness, soreness, and hyperalgesia (increased pain intensity in response to the same noxious stimulus; e.g. moderate pressure causes severe pain). A striking example of sensitization is sunburned skin, in which severe pain can be produced by a gentle slap on the back or a warm shower.
Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate significant discomfort when distended. In contrast, when affected by a disease process with an inflammatory component, deep structures such as joints or hollow viscera characteristically become exquisitely sensitive to mechanical stimulation.
A large proportion of Aδ and C fiber afferents innervating viscera are completely insensitive in normal noninjured, noninflamed tissue. That is, they cannot be activated by known mechanical or thermal stimuli and are not spontaneously active. However, in the presence of inflammatory mediators, these afferents become sensitive to mechanical stimuli. Such afferents have been termed silent nociceptors, and their characteristic properties may explain how, under pathologic conditions, the relatively insensitive deep structures can become the source of severe and debilitating pain and tenderness. Low pH, prostaglandins, leukotrienes, and other inflammatory mediators such as bradykinin play a significant role ...