Some cutaneous sensory receptors are not specialized organs but rather they are free nerve endings. Pain and temperature sensations arise from unmyelinated dendrites of sensory neurons located throughout the glabrous and hairy skin as well as deep tissue. Nociceptors can be separated into several types. Mechanical nociceptors respond to strong pressure (eg, from a sharp object). Thermal nociceptors are activated by skin temperatures above 42°C or by severe cold. Chemically sensitive nociceptors respond to various chemicals such as bradykinin, histamine, high acidity, and environmental irritants. Polymodal nociceptors respond to combinations of these stimuli.
Impulses from nociceptors are transmitted via two fiber types, thinly myelinated Aδ fibers (2–5 μm in diameter) that conduct at rates of ~12–35 m/s and unmyelinated C fibers (0.4–1.2 μm in diameter) that conduct at low rates of ~0.5–2 m/s. Activation of Aδ fibers, which release glutamate, is responsible for first pain (also called fast pain or epicritic pain), which is a rapid response and mediates the discriminative aspect of pain or the ability to localize the site and intensity of the noxious stimulus. Activation of C fibers, which release a combination of glutamate and substance P, is responsible for the delayed second pain (also called slow pain or protopathic pain), which is the dull, intense, diffuse, and unpleasant feeling associated with a noxious stimulus. Itch and tickle are also related to pain sensation.
There are a variety of receptors located on the endings of nociceptive sensory nerves that respond to noxious thermal, mechanical, or chemical stimuli (Figure 1). Many of these are part of a family of nonselective cation channels called transient receptor potential (TRP) channels. This includes TRPV1 receptors (the V refers to a group of chemicals called vanil loids) that are activated by intense heat, acids, and chemicals such as capsaicin (the active principle of hot peppers and an example of a vanilloid). TRPV1 receptors can also be activated indirectly by initial activation of TRPV3 receptors in keratinocytes in the skin. Noxious mechanical, cold, and chemical stimuli may activate TRPA1 receptors (A, for ankyrin) on sensory nerve terminals. Sensory nerve endings also have acid sensing ion channel (ASIC) receptors that are activated by pH changes within a physiologic range and may be the dominant receptors mediating acid-induced pain. In addition to direct activation of receptors on nerve endings, some nociceptive stimuli release intermediate molecules that then activate receptors on the nerve ending. For example, nociceptive mechanical stimuli cause the release of adenosine triphosphate (ATP) that acts on purinergic receptors (eg, P2X, an ionotropic receptor, and P2Y, a G-protein–coupled receptor). Tyrosine receptor kinase A (TrkA) is activated by nerve growth factor (NGF) that is released as a result of tissue damage.
Fig1. Receptors on nociceptive unmyelinated nerve terminals in the skin. Nociceptive stimuli (eg, heat) can activate some receptors directly due to transduction of the stimulus energy by receptors (eg, transient receptor potential (TRP) channel TRPV1) or indirectly by activation of TRP channels on keratinocytes (eg, TRPV3). Nociceptors (eg, mechanoreceptors) can also be activated by the release of intermediate molecules (eg, ATP). ASIC, acid-sensitive ion channel; P2X, ionotropic purinoceptor; P2Y, G-protein–coupled purinergic receptor.
Nerve endings also have a variety of receptors that respond to immune mediators that are released in response to tissue injury. These include B1 and B2 receptors (brady kinin), prostanoid receptors (prostaglandins), and cytokine receptors (interleukins). These receptors mediate inflammatory pain.
