THE PAIN SENSORY SYSTEM

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 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.

PERIPHERAL MECHANISMS
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. 1-1). The cell bodies of primary sensory afferents are located in the dorsal root ganglia in the vertebral foramina. The primary afferent axon bifurcates to send one process into the spinal cord and the other to innervate tissues. Primary afferents are classified by their diameter, degree of myelination, and conduction velocity. The largest-diameter fibers, A-beta (Ab), 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 (Ad) and the unmyelinated (C fiber) axons (Fig. 1-1). 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 Ad and C afferents. Most Ad and C 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 Ad and C axons are blocked. Individual primary afferent nociceptors can respond to several different types of noxious stimuli. For example, most nociceptors respond to heating, intense cold, intense mechanical stimuli such as a pinch, and application of irritating chemicals including ATP, serotonin, bradykinin and histamine.

FIGURE 1-1 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 (Ab), small-diameter myelinated (Ad), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.

Sensitization: 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. In sensitized tissues, normally innocuous stimuli can produce pain. Sensitization is a clinically important process that contributes to tenderness, soreness, and hyperalgesia. 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 Ad and C 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 in sensitization.

FIGURE 1-2 Events leading to activation, sensitization, and spread of sensitization of primary afferent nociceptor terminals.
A. Direct activation by intense pressure and consequent cell damage. Cell damage induces lower pH (H+) and leads to release of potassium (K+) and to synthesis of prostaglandins (PG) and bradykinin (BK). Prostaglandins increase the sensitivity of the terminal to bradykinin and other pain-producing substances.

Nociceptor-Induced Inflammation: Primary afferent nociceptors also have a neuroeffector function. Most nociceptors contain polypeptide mediators that are released from their peripheral terminals when they are activated (Fig. 1-2). An example is substance P, an 11-amino-acid peptide. Substance P is released from primary afferent nociceptors and has multiple biologic activities. It is a potent vasodilator, degranulates mast cells, is a chemoattractant for leukocytes, and increases the production and release of inflammatory mediators. Interestingly, depletion of substance P from joints reduces the severity of experimental arthritis. Primary afferent nociceptors are not simply passive messengers of threats to tissue injury but also play an active role in tissue protection through these neuroeffector functions.

B. Secondary activation. Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP). Substance P causes vasodilation and neurogenic edema with further accumulation of bradykinin. Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets.