Although somewhat confusing, the term nociceptor is used to refer both to the free nerve terminals of primary afferent fibers that respond to painful, potentially injurious stimuli and to the entire apparatus (sensory neuron, including free terminals) capable of transducing and transmitting information about noxious stimuli. In this chapter, the term nociceptor is used to refer to the entire nociceptive primary afferent.

Free nerve terminals contain receptors capable of transducing chemical, mechanical, and thermal signals. Recently, for example, a membrane receptor that responds to noxious heat has been cloned (it has been designated TRPV1), and, interestingly, this receptor is also stimulated by capsacin, the molecule responsible for the “hot” sensation associated with hot peppers. Nociceptive terminals innervate a wide variety of tissues and are present in both somatic and visceral structures including the cornea, tooth pulp, muscles, joints, respiratory system, cardiovascular system, digestive system, urogenital system, and meninges, as well as skin.

Nociceptors may be divided according to three criteria: degree of myelination, type(s) of stimulation that evokes a response, and response characteristics. There are two basic classes of nociceptors based on their degree of myelination and conduction velocity. A-delta fibers (Aδ) are thinly myelinated and conduct at a velocity of 2 to 30 m per second. C fibers are unmyelinated and conduct at a velocity of less than 2 m per second (see Table 1). Aδ and C nociceptors can be further divided according to the stimuli they sense. These nociceptors may respond to mechanical, chemical, or thermal (heat and cold) stimuli, or a combination (polymodal). For example, C-fiber mechanoheat receptors respond to noxious mechanical stimuli and intermediate heat stimuli (41°C to 49°C), have a slow conduction velocity, and constitute most nociceptive afferent fibers. Aδ mechanoheat receptors can be divided into two subtypes. Type I receptors have a high heat threshold (>53°C) and conduct at relatively fast velocities (30 to 55 m per second). These receptors detect pain during high-intensity heat responses. Type II receptors have a lower heat threshold and conduct at slower velocity (15 m per second). Some receptors respond to both warmth and thermal pain. Some C and Aδ fibers are mechanically insensitive but respond to heat, cold, or a variety of chemicals (e.g., bradykinin, hydrogen ions, serotonin, histamine, arachidonic acid, and prostacyclin).

The neural impulses originating from the free endings of nociceptors are transmitted via primary afferent nerves to the spinal cord, or, if originating from the head and neck, the impulses are transmitted via cranial nerves to the brainstem. Most primary afferent fibers of innervating tissues below the head have cell bodies located in the dorsal root ganglion (DRG) of spinal nerves. Primary afferent fibers of cranial nerves V, VII, IX, and X (the sensory cranial nerves) have cell bodies in their respective sensory ganglia.

Most nociceptors are C fibers, and 80% to 90% of C fibers respond to nociceptive input. The differences in conduction velocities and response characteristics of Aδ and C fibers may explain the typical subjective experience of pain associated with a noxious stimulus: a first pain (so-called epicritic pain) that is rapid, well localized, and pricking in character (Aδ), followed by a second pain (so-called protopathic pain) that is burning and diffuse (C fiber). Visceral afferent nociceptive fibers (Aδ and C) travel with sympathetic and parasympathetic fibers; their cell bodies are also found in the DRG. Muscle is also innervated by both Aδ and C fibers, and, interestingly, muscle pain appears to be limited in quality to that of a cramp.

Primary afferent nociceptors enter the spinal cord via Lissauer tract and synapse on neurons in the dorsal horn (see Fig. 1). Lissauer tract is a bundle of predominantly (80%) primary afferent fibers, consisting mainly of Aδ and C fibers that penetrate the spinal cord en route to the dorsal horn. After entering the spinal cord, Aδ and C fibers run up or down one or two segments before synapsing with second-order neurons in the dorsal horn. The dorsal horn synapse is an important site of further processing and integration of the incoming nociceptive information. The dorsal horn may be a point at which nociceptive information is conducted to higher centers, or a point at which nociceptive information is inhibited by descending systems. The responsiveness of dorsal horn neurons may change in response to prior noxious afferent input, particularly repetitive input (central sensitization).

Prolonged noxious stimulation can sensitize nociceptors. Sensitization refers to a decreased threshold as well as to an increased response to suprathreshold stimulation. It is observed following direct nerve injury and inflammation and is the result of a complex set of transcriptional and posttranslational changes in the primary nociceptive afferents. Sensitization of the entire nociceptive pathway can arise secondary to changes in the CNS (central sensitization) or the periphery (peripheral sensitization). Once sensitization is established, it is often impossible to clinically separate central from peripheral contributions to the process of sensitization. The related topics on hyperalgesia, allodynia, inflammation, and nerve injury are briefly discussed in the following text.