In terms of peripheral pain mechanisms, there is indeed a degree of specificity of pain conducting nerve fibers. In keeping with distinctions between nerve types, the sensory fibers have been classified according to their size and function (Table 7-1). It is well established that two types of afferent fibers in the distal axons of primary sensory neurons respond maximally to nociceptive (i.e., potentially tissue-damaging) stimuli. One type is the very fine, unmyelinated, slowly conducting C fiber (0.3–1.1 μ in diameter); the other is the thinly myelinated, more rapidly conducting A-d fiber (2–5 μ in diameter). The peripheral terminations of both of these primary pain afferents, or receptors, are free, profusely branched nerve endings in the skin and other organs; these are covered by Schwann cell cytoplasm but little or no myelin.
There is considerable evidence, based on physiologic responses, that a degree of subspecialization exists within these freely branching, nonencapsulated endings and their small-fiber afferents. Three categories of free endings or receptors are recognized: mechanoreceptors, thermoreceptors, and polymodal nociceptors. Each ending transduces stimulus energy into an action potential in the distal nerve membranes. The first two types of receptors are activated by innocuous mechanical and thermal stimulation, respectively; the mechanoeffects are transmitted by both A-d and C fibers and the thermal effects mostly by
C fibers. The majority of C-fiber endings are polymodal and are most effectively excited by noxious or tissue-damaging stimuli, but they can also respond to mechanical or thermal stimuli and to chemical mediators such as those associated with inflammation. Moreover, certain A-d fibers respond to light touch, temperature, and pressure as well as to pain stimuli and are capable of discharging in proportion to the intensity of the stimulus. The stimulation of single fibers by intraneural electrodes indicates that they can also convey information concerning the nature and location of the stimulus. These observations on the polymodal functions of A-d and C fibers would explain the observations of Lele and Weddell and of Weddell that modes of sensation other than pain can be evoked from structures such as the cornea, which is innervated solely by free nerve endings.
The manner in which painful stimuli are translated into electrical depolarizations in nerve endings is beginning to be understood. A number of specialized molecules, when activated by noxious stimuli, open cationic channels in membranes of the nerve ending. Opening of these channels activates voltage-gated sodium channels and generates an action potential in the sensory axon. It is of interest that numerous specialized ion channels are expressed only on some nociceptive nerve cells and their processes, but not in the brain or spinal cord; these include unique sodium, potassium, calcium channels, and other cation channels such as TRP (transient receptor potential) and ASIC (acid sensing ion channel). Benarroch has summarized the regulation and activation of these receptor molecules. Particular pain syndromes arise from mutations in these channels and from autoimmune diseases that interfere with their function.