Primary afferent nociceptors

A peripheral nerve contains axons that differ widely in their cross-sectional diameter, degree of myelination and conduction velocity (CV). The axons of the primary afferents fall into three distinct groups: A-β (diameter 6–22 μm, heavily myelinated, CV 33–75 m/s), A-δ (diameter 2–5 μm, thinly myelinated, CV 5–30 m/s) and C fibers (diameter 0.3–3 μm, unmyelinated, CV 0.5–2 m/s) [1,2]. To which of these axonal groups classes do the primary afferent nociceptors belong?

At one level, there is a straightforward experimental approach to this question. One needs only to determine the response properties of an afferent and measure its conduction velocity. In fact, cutaneous nociceptors are defined by their characteristic discharge pattern. Using mechanical or thermal stimuli, PANs discharge when the stimulus intensity is at or above the level reported as painful when delivered to the normal skin of a human subject. Characteristically, PANs discharge with increasing frequency to stimuli of increasing intensity within the range reported as painful (Figure 1.1). Using these criteria most PANs fall into one of two groups of afferents: the unmyelinated C fibers and small-diameter myelinated or A-δ group (see Chapter 2 for details). Few, if any, belong to the A-β group.

The large myelinated primary afferents in the A-β group respond to low-intensity mechanical stimuli and show no increase in discharge frequency to more intense stimuli. Thus the A-β fibers cannot selectively signal the presence of potentially tissue-damaging stimuli. Consistent with this is the observation that in awake human subjects, electrical stimulation of A-β afferents elicits sensations that are not painful. In fact, there is evidence that selective activation of A-β afferents may actually inhibit nociceptive transmission at the spinal level [3,4].

Despite the evidence against a positive contribution of A-β afferents to pain perception, recent studies suggest that, under certain conditions, especially when there is nerve damage, activity in A-β afferents can elicit pain (e.g. see the discussions by Roberts and Kramis in Chapter 4 and by Raja, Meyer and Campbell in Chapter 2 in this book). Thus, although activity of PANs is sufficient to elicit the sensation of pain, it is likely that activity of PANs is not always required for a stimulus to evoke pain. This illustrates the crucial point that the term nociceptor refers to the type of stimuli to which a particular primary afferent responds, as opposed to the type of sensation it produces when it is active. Under normal conditions, nociceptors respond to intense stimuli and, when they are active, consistently elicit the sensation of pain. Under pathological conditions, activity in afferents that are not nociceptors can elicit pain.

The peripheral terminals of primary afferent nociceptors are sensitive to one or more of the following types of stimulus: thermal, mechanical or chemical. The most ubiquitous PAN can be activated by all three types of stimuli and is thus termed the polymodal nociceptor. Most polymodal nociceptors have axons that are unmyelinated. The other major classes of PAN respond only to relatively intense mechanical (high-threshold mechanoreceptors) or to both intense mechanical and thermal stimuli (mechanothermal nociceptors). The latter two classes of nociceptor usually have axons that are myelinated.

Normally, PANs have no spontaneous activity in the absence of stimulation and do not discharge in response to stimuli that are innocuous when applied to normal skin [5]. However, the response properties of primary afferent nociceptors are dependent on previous stimuli. Most nociceptors become sensitized by tissue-damaging stimuli in the region of their terminals. This property of nociceptors is reviewed extensively in Chapter 2 of this book. Suffice it to say that, in a region of injury, some PANs undergo prolonged changes which result in a lowering of their threshold for activation (producing tenderness and hyperalgesia) and others become spontaneously active (producing continuous pain that outlasts the stimulus producing it).

Pain-producing substances

Most clinically significant pains have a time course of hours to days, far beyond the duration of the usual stimuli employed to study nociceptors in the experimental situation. In addition, clinical pains are accompanied by tenderness and, often, hypersensitivity. Tenderness and hyperalgesia simply mean that stimuli that are normally painful are even more painful. There are several contributors to tenderness and hyperalgesia. In part they reflect the sensitization of PANs (a shift to the left of the stimulus intensity–PAN discharge curve). It is likely that intense stimuli also elicit long-lasting changes in the central nervous system that enhance pain transmission...