The particular receptor class expressed in the nerve terminal of a sensory neuron determines the type of stimulus detected by the neuron. The peripheral axons of the sensory neurons that mediate touch and proprioception terminate in a nonneural capsule. They sense mechanical stimuli that indent or otherwise physically deform the receptive surface. In contrast the peripheral axons of neurons that detect noxious, thermal, or chemical events have unsheathed endings with multiple branches.
When a somatic receptor is activated by an appropriate stimulus, the terminal of the sensory neuron is typically depolarized. Stimuli of sufficient strength produce action potentials that are transmitted along the peripheral branch of the neuron's axon and into the central branch that terminates in the spinal cord or brain stem.
A variety of morphologically specialized receptors underlie the various somatosensory submodalities. For example, the median nerve that innervates the skin of the hand and some of the muscles controlling the hand contains tens of thousands of nerve fibers that can be classified into 30 functional types. Of these, 22 types are afferent fibers (sensory axons conducting impulses toward the spinal cord), and eight types are efferent fibers (motor axons conducting impulses away from the spinal cord to skeletal muscle, blood vessels, and sweat glands). The afferent fibers convey signals from eight kinds of cutaneous mechanoreceptors that are sensitive to different kinds of skin deformation; five kinds of proprioceptors that signal information about muscle force, muscle length, and joint angle; four thermoreceptors that report the temperatures of objects touching the skin; four nociceptors that signal potentially injurious stimuli; and at least one kind of itch receptor. The major receptor groups within each submodality are listed in Table 22–2.
Table 22–2Receptor Types Active in Somatic Sensation ||Download (.pdf) Table 22–2 Receptor Types Active in Somatic Sensation
|Receptor type ||Fiber group 1 ||Fiber name ||Modality |
|Cutaneous and subcutaneous mechanoreceptors || || ||Touch |
| Meissner corpuscle ||Aα,β ||RA1 || Stroking, flutter |
| Merkel disk receptor ||Aα,β ||SA1 || Pressure, texture |
| Pacinian corpuscle2 ||Aα,β ||RA2 || Vibration |
| Ruffini ending ||Aα,β ||SA2 || Skin stretch |
| Hair-tylotrich, hair-guard ||Aα,β ||G1, G2 || Stroking, fluttering |
| Hair-down ||Aδ ||D || Light stroking |
| Field ||Aα,β ||F || Skin stretch |
| C mechanoreceptor ||C || || Stroking, erotic touch |
|Thermal receptors || || ||Temperature |
| Cool receptors ||Aδ ||III || Skin cooling (<25°C [77°F]) |
| Warm receptors ||C ||IV || Skin warming (>35°C [95°F]) |
| Heat nociceptors ||Aδ ||III || Hot temperature (>45°C [113°F]) |
| Cold nociceptors ||C ||IV || Cold temperature (<5°C [41°F]) |
|Nociceptors || || ||Pain |
| Mechanical ||Aδ ||III || Sharp, pricking pain |
| Thermal-mechanical (heat) ||Aδ ||III || Burning pain |
| Thermal-mechanical (cold) ||C ||IV || Freezing pain |
| Polymodal ||C ||IV || Slow, burning pain |
|Muscle and skeletal mechanoreceptors || || ||Limb proprioception |
| Muscle spindle primary ||Aα ||Ia || Muscle length and speed |
| Muscle spindle secondary ||Aβ ||II || Muscle stretch |
| Golgi tendon organ ||Aα ||Ib || Muscle contraction |
| Joint capsule receptors ||Aβ ||II || Joint angle |
| Stretch-sensitive free endings ||Aδ ||III || Excess stretch or force |
Mechanoreceptors Mediate Touch and Proprioception
Mechanoreceptors sense physical deformation of the tissue in which they reside. Mechanical distension, such as pressure on the skin or stretch of muscles, is transduced into electrical energy by the physical action of the stimulus on cation channels in the membrane. Mechanical stimulation deforms the receptor protein, thus opening stretch-sensitive ion channels and increasing Na+ and Ca2+ conductances that depolarize the receptor neuron. Removal of the stimulus relieves mechanical stress on the receptor and allows stretch-sensitive channels to close.
Some mechanoreceptor ion channels are activated directly by forces applied to the tissue, permitting rapid activation and inactivation. For example, Pacinian corpuscle receptors in the skin can respond to vibration at frequencies as high as 500 Hz, firing one impulse for each vibratory cycle. This means that the receptor is capable of firing an impulse every 2 ms for sustained periods.
Various mechanisms for direct activation of mechanoreceptor ion channels have been proposed. Some mechanoreceptors appear to respond to forces conveyed through tension in the lipids of the plasma membrane (Figure 22–4A). This may be the mechanism for detection of cellular swelling, which plays an important role in osmoregulation.
Ion channels in mechanoreceptor nerve terminals are activated by mechanical stimuli that stretch or deform the cell membrane.
Mechanical displacement leads to channel opening, permitting the influx of cations. (Modified, with permission, from Lin and Corey 2005.)
A. Channels can be directly activated by forces conveyed through lipid tension in the cell membrane, such as osmotic swelling.
B. Forces conveyed through structural proteins linked to the ion channel can also directly activate channels. The linking proteins may be either extracellular (attached to the surrounding tissue) or intracellular (bound to the cytoskeleton) or both.
C. Channels can be indirectly activated by forces conveyed to a force sensor (a separate protein) in the membrane. An internal second messenger carries the sensory signal from the mechanosensitive protein to the channel.
Another mechanism for direct activation of mechanoreceptors is linking the channel to the surrounding tissue of the skin or to muscle cell membranes through structural proteins. The extracellular linkage is elastic and often represented as a spring, whereas the intracellular portion of the channel is anchored directly to proteins of the cytoskeleton (Figure 22–4B). Direct channel gating in this model may be produced by forces perpendicular or parallel to the receptor cell membrane that stretch the extracellular linkage protein. This type of direct channel gating may be used by hair cells of the inner ear. Similar mechanical linkages between the skin and cutaneous mechanoreceptors have been postulated.
Likewise, mechanical coupling of sensory nerve terminals to skeletal muscle or tendons is thought to underlie proprioception. Unfortunately, because these receptors are embedded in nonneural tissue and thus difficult to isolate for biochemical analysis, the proteins involved in transduction have not been identified in mammals. Studies of invertebrates suggest that the transduction molecules for mechanosensation in skin and muscle may belong to the degenerin superfamily, which includes ion channels related to vertebrate epithelial Na+ channels.
Some mechanoreceptor ion channels are activated indirectly through second-messenger pathways. In this case the force sensor in the receptor's cell membrane is a protein distinct from the ion channel (Figure 22–4C). A variety of intracellular messengers signal stimulation of the sensor to the ion channel, causing the channel to open. Unlike direct activation, the indirect pathway is slow to activate and inactivate, often outlasting the stimulus. The great advantage of the second-messenger mechanism of course is that the sensory signal is amplified; the conductance of many ionic channels can be affected by the activation of a single sensor molecule in the receptor cell. These properties are consistent with the responses of pain receptors sensitive to mechanical damage of the skin, such as pinch, or excessive distension of viscera. David Corey and co-workers have suggested that these sensations are mediated by TRPV4 receptors, a class of transient receptor potential (TRP) receptors that are also involved in thermal senses (see below).
The specialized, nonneural end organ that surrounds the nerve terminal of a mechanoreceptor nerve must be deformed in specific ways to excite the nerve. For example, individual receptors may respond selectively to pressure or motion, and may detect the direction of force applied to the skin, joints, or muscle fibers. The end organ can also amplify or modulate the sensitivity of the receptor to mechanical displacement.
The skin has eight types of mechanoreceptors that are responsible for the sense of touch (see Table 22–2). They are described briefly here and in greater detail in Chapter 23. The glabrous skin of the hands and feet contains four kinds of mechanoreceptors: Meissner corpuscles, Merkel cells, Pacinian corpuscles, and Ruffini endings (Figure 22–5). Two of these receptors are classified as slowly adapting (SA) because they continue to fire in response to steady pressure on the skin. The other two receptors are rapidly adapting (RA), responding to motion on the skin but not to steady pressure. They also differ in receptor size and location within the skin.
Touch is mediated by four types of mechano receptors in the human hand.
The terminals of myelinated sensory nerves innervating the hand are surrounded by specialized structures that detect contact on the skin. The receptors differ in morphology, innervation patterns, location in the skin, receptive field size, and physiological responses to touch. (Adapted, with permission, from Johansson and Vallbo 1983.)
A. The superficial and deep layers of the glabrous (hairless) skin of the hand each contain distinct types of mechanoreceptors. The superficial layers contain small receptor cells: Meissner corpuscles and Merkel cells. The sensory nerve fibers innervating these receptors have branching terminals such that each fiber innervates multiple receptors of one type. The deep layers of the skin and subcutaneous tissue contain large receptors: Pacinian corpuscles and Ruffini endings. Each of these receptors is innervated by a single nerve fiber, and each fiber innervates only one receptor. The receptive field of a mechanoreceptor reflects the location and distribution of its terminals in the skin. Touch receptors in the superficial layers of the skin have smaller receptive fields than those in the deep layers. (RA1, rapidly adapting type 1; RA2, rapidly adapting type 2; SA1, slowly adapting type 1; SA2, slowly adapting type 2.)
B. The nerve fibers innervating each type of mechanoreceptor respond differently when activated. The spike trains show responses of each type of nerve when its receptor is activated by constant pressure against the skin. The RA type fibers that innervate Meissner and Pacinian corpuscles adapt rapidly to constant stimulation while the SA type nerves that innervate Merkel cells and Ruffini endings adapt slowly.
Merkel cells are innervated by slowly adapting type 1 (SA1) fibers. They signal the amount of pressure applied to the skin and are particularly sensitive to edges, corners, and points. They distinguish textures and play key roles in the ability to read Braille. The Ruffini endings are innervated by slowly adapting type 2 (SA2) fibers. These receptors respond more vigorously to stretch than to indentation of skin, and consequently are particularly sensitive to the shape of large objects held in the hand. They also signal movements of the fingers and other joints that stretch the overlying skin.
Meissner corpuscles are innervated by rapidly adapting type 1 (RA1) fibers. These receptors detect the initial contact of the hand with objects, slippage of objects held in the hand, motion of the hand over textured surfaces, and low-frequency vibration. The Pacinian corpuscles are innervated by rapidly adapting type 2 (RA2) fibers. The receptor is a large, onion-like capsule that surrounds the axon terminal. It responds to motion in the nanometer range and mediates high-frequency vibration. The most important role of Pacinian corpuscles is detection of vibrations in tools, objects, or probes held in the hand.
The general hairy skin includes all of the mechanoreceptor organs of the glabrous skin except the Meissner corpuscle; the hair follicle afferents serve a function similar to that of Meissner corpuscles. Hair follicle afferents innervate 10 to 30 hairs spread over an area of 1 to 2 cm2 and are sensitive to hair movement but not to static pressure. Other mechanoreceptors of the hairy skin include field receptors, which are very sensitive to skin movement, and low-threshold mechanoreceptors innervated by C fibers that respond to slow stroking of the skin and are thought to mediate erotic touch.
Proprioceptors Measure Muscle Activity and Joint Positions
Mechanoreceptors in muscles and joints convey information about the posture and movements of the body and thereby play an important role in proprioception and motor control. These receptors include two types of muscle-length sensors, the type Ia and II muscle-spindle endings; one muscle force sensor, the Golgi tendon organ; and joint-capsule receptors, which transduce tension in the joint capsule.
The muscle spindle consists of a bundle of thin muscle fibers, or intrafusal fibers, that are aligned parallel to the larger fibers of the muscle and enclosed within a capsule (Figure 22–6A). The intrafusal fibers are entwined by a pair of sensory axons that detect muscle stretch because of mechanoreceptive ion channels in the nerve terminals. Intrafusal muscles are also innervated by motor neurons that determine contractile force. (See Box 35–1 for details on muscle spindles.)
The muscle spindle is the principal receptor mediating proprioception.
A. The muscle spindle is located within skeletal muscle and is excited by stretch of the muscle. It consists of a bundle of thin (intrafusal) muscle fibers entwined by a pair of sensory axons, and is also innervated by several motor axons (not shown) that produce contraction of the intrafusal muscle fibers. Stretch-sensitive ion channels in the sensory nerve terminals are linked to the cytoskeleton by the protein spectrin. (Adapted, with permission, from Sachs 1990.)
B. The depolarizing receptor potential recorded in a group Ia fiber innervating the muscle spindle (upper record) is proportional to both the velocity and amplitude of muscle stretch parallel to the myofilaments (lower record). When stretch is maintained at a fixed length, the receptor potential decays to a lower value. (Adapted, with permission, from Ottoson and Shepherd 1971.)
C. Patch clamp recordings of a single stretch-sensitive channel in myocytes. Pressure is applied to the receptor cell membrane by suction. At rest (top record) the channel opens sporadically for short time intervals. As the pressure applied to the membrane increases (lower records) the channel opens more often and remains in the open state longer. This allows more current to flow into the receptor cell, resulting in higher levels of depolarization. (Adapted, with permission, from Sachs 1990.)
Although the receptor potential and firing rates of the sensory axons are proportional to muscle length (Figure 22–6B), these responses can be modulated by higher centers in the brain that regulate contraction of intrafusal muscles. In this manner the spindle afferents are able to signal the amplitude and speed of internally generated voluntary movements as well as passive limb displacement by external forces.
Golgi tendon organs, located between skeletal muscle and tendons, measure the forces generated by muscle contraction. (See Box 35–3 for details on Golgi tendon organs.) Although these receptors play an important role in reflex circuits modulating muscle force, they appear to contribute little to conscious sensations of muscle activity. Psychophysical experiments in which muscles are fatigued or partially paralyzed have shown that perceived muscle force is mainly related to centrally generated effort rather than to actual muscle force.
Joint receptors play little if any role in postural sensations of joint angle. Instead, the perception of the angle of proximal joints such as the elbow or knee depends on afferent signals from muscle spindle receptors and efferent motor commands. Likewise, conscious sensations of finger position and hand shape depend on stretch receptors in the skin as well as muscle spindles and possibly joint receptors.
The receptors that respond selectively to stimuli that can damage tissue are called nociceptors (Latin nocere, to injure). They respond directly to mechanical and thermal stimuli, and indirectly to other stimuli by means of chemicals released from cells in the traumatized tissue. Nociceptors signal impending tissue injury and, more importantly, they provide a constant reminder of tissues that are already injured and must be protected.
Nociceptors in the skin, muscle, joints, and visceral receptors fall into two broad classes based on the myelination of their afferent fibers. Nociceptors innervated by Aδ fibers produce short-latency pain that is described as sharp and pricking. The majority are called mechanical nociceptors because they are excited by sharp objects that penetrate, squeeze, or pinch the skin (Figure 22–7). Many of these AΔ fibers also respond to noxious heat that can burn the skin.
Mechanical nociceptors respond to stimuli that puncture, squeeze, or pinch the skin.
Sensations of sharp, pricking pain result from stimulation of AΔ fibers with free nerve endings in the skin. These receptors respond to sharp objects that puncture the skin (B) but not to strong pressure from a blunt probe (A). The strongest responses are produced by pinching the skin with serrated forceps that damage the tissue in the region of contact (C). (Adapted, with permission, from Perl 1968.)
Nociceptors innervated by C fibers produce dull, burning pain that is diffusely localized and poorly tolerated. The most common type are polymodal noci ceptors that respond to a variety of noxious mechanical, thermal, and chemical stimuli, such as pinch or puncture, noxious heat and cold, and irritant chemicals applied to the skin. Electrical stimulation of these fibers in humans evokes prolonged sensations of burning pain. In the viscera nociceptors are activated by distension or swelling, producing sensations of intense pain.
Thermal Receptors Detect Changes in Skin Temperature
Although the size, shape, and texture of objects held in the hand can be apprehended visually as well as by touch, the thermal qualities of objects are uniquely somatosensory. Humans recognize four distinct types of thermal sensation: cold, cool, warm, and hot. These sensations result from differences between the external temperature of the air or of objects contacting the body and the normal skin temperature of approximately 32°C (90°F).
Although we are exquisitely sensitive to sudden changes in skin temperature, we are normally unaware of the wide swings in skin temperature that occur as our cutaneous blood vessels open and close to discharge or conserve body heat. If skin temperature changes slowly, we are unaware of changes in the range 31°to 36°C (88–97°F). Below 31°C (88°F) the sensation progresses from cool to cold and finally, beginning at 10°to 15°C (50–59°F), to pain. Above 36 C (97 F) the sensation progresses from warm to hot and then, beginning at 45°C (113°F), to pain.
Thermal sensations result from the combined activity of six types of afferent fibers: low-threshold and high-threshold cold receptors, warm receptors, and two classes of heat nociceptors. The low-threshold cold receptor fibers are small-diameter, myelinated AΔ fibers with unmyelinated endings within the epidermis. They are approximately 100 times more sensitive to sudden drops in skin temperature than to gradual changes. This extreme sensitivity to change allows humans to detect a draft from a distant open window. The high-threshold cold receptor fibers are much less sensitive to small cooling changes, but can signal rapid skin cooling even below 0°C (32°F).
The various qualities of cold sensations can be experienced by grasping an ice cube in a closed fist. Over the first five seconds or so the sensation progresses from cool to cold. After 10 seconds the sensation becomes progressively more painful. If the ice is held still longer, the sensation begins to include a deep, aching quality. The low-threshold and high-threshold receptors account for the initial sensations; the aching cold pain likely results from receptors within the veins.
Warm receptors are located in the terminals of C fibers that end in the dermis. Unlike the cold receptors, warm receptors act more like simple thermometers; their firing rates rise monotonically with increasing skin temperature up to the threshold of pain and then saturate at higher temperatures. Thus they cannot play a role in signaling heat pain. They are much less sensitive to rapid changes in skin temperature than are cold receptors. Consequently, humans are less responsive to warming than cooling; the threshold for detecting sudden skin warming, even in the most sensitive subject, is about 0.1 Centigrade degree.
Heat nociceptors are activated by temperatures exceeding 45°C (113°F) and inactivated by skin cooling. The burning pain caused by high temperatures is transmitted by both myelinated Aδ fibers and unmyelinated C fibers.
Recent studies by David Julius and his colleagues revealed that thermal stimuli activate specific classes of TRP ion channels in the membrane. These nonselective cation receptor-channels are similar in structure to voltage-gated channels. They have four protein subunits, each of which contains six transmembrane domains, with a pore between the fifth and sixth segments. Both the C and N terminals are located in the cytoplasm. Individual TRP receptor-channels are distinguished by their sensitivity to heat or cold, showing sharp increases in conductance to cations when their thermal threshold is exceeded (Figure 22–8). Their names specify the genetic subfamily of TRP receptors and the member number. Examples include TRPV1 (for TRP vanilloid-1), TRPM8 (for TRP melastatin-8), and TRPA1 (for TRP ankyrin-1).
Transient receptor potential ion channels.
Transient receptor potential (TRP) channels are membrane proteins with six transmembrane domains. A pore is formed between the fifth (S5) and sixth (S6) segments. Both C- and N-terminals are located in the cytoplasm. Most of these receptors contain ankyrin repeats in the N-terminal domains and a common 25-amino acid motif adjacent to S6 in the C-terminal domain. All TRP channels are gated by temperature and various chemical ligands, but different types respond to different temperature ranges and have different activation thresholds. At least six types of TRP receptors have been identified in sensory neurons; the thermal sensitivity of a neuron is determined by the particular TRP receptors expressed in its nerve terminals.
At 32°C (90°F), the resting skin temperature (asterisk), only TRPV4 and some TRPV3 receptors are stimulated. TRPA1 and TRPM8 receptors are activated by cooling and cold stimuli. TRPM8 receptors also respond to menthol and various mints; TRPA1 receptors respond to alliums such as garlic and radishes. TRPV3 receptors are activated by warm stimuli and also bind camphor. TRPV1 and TRPV2 receptors respond to heat and produce burning pain sensations. TRPV1 but not TRPV2 receptors bind capsaicin, which mediates the burning sensations evoked by chili peppers. TRPV4 receptors are active at normal skin temperatures and respond to touch. (Adapted, with permission, from Jordt, McKemy, and Julius 2003; Dhaka, Viswanath, and Patapoutian 2006.)
Two classes of TRP receptors are activated by cold temperatures and inactivated by warming. TRPM8 receptors respond to temperatures below 25°C (77°F); such temperatures are perceived as cool or cold. TRPA1 receptors have thresholds below 17°C (63°F); this range is described as cold or frigid. Both TRPM8 and TRPA1 receptors are expressed in high-threshold cold receptor terminals, but only TRPM8 receptors are expressed in low-threshold cold receptor terminals.
Four types of TRP receptors are activated by warm or hot temperatures and inactivated by cooling. TRPV3 receptors are expressed in warm type fibers; they respond to warming of the skin above 35°C (95°F) and generate sensations ranging from warm to hot. TRPV1 and TRPV2 receptors respond to temperatures exceeding 45°C (113°F) and mediate sensations of burning pain; they are expressed in heat nociceptors. TRPV4 receptors are activated by temperatures above 27 C and respond to normal skin temperatures. They may play a role in touch sensation.
The role of TRP receptors in thermal sensation was originally discovered by analyses of natural substances such as capsaicin and menthol that produce burning or cooling sensations when applied to the skin or injected subcutaneously. Capsaicin, the active ingredient in chili peppers, has been used extensively to activate nociceptive afferents that mediate sensations of burning pain. These studies indicate that the various TRP receptors also bind other molecules that induce painful sensations, such as toxins, venoms, and substances released by diseased or injured tissue. These substances act by covalent modification of cysteines in the TRP channel protein.
Itch Is a Distinctive Cutaneous Sensation
Itch is a common sensory experience that is confined to the skin, the ocular conjunctiva, and the mucosa. Itch has some properties in common with pain and until recently was thought to result from low firing rates in nociceptive fibers. Like pain, itch is inherently unpleasant whatever its intensity; even at the expense of inducing pain, we attempt to eliminate it by scratching. When nerve conduction is blocked with pressure, itch persists until the slowest unmyelinated fibers stop firing.
Itch can be induced either by the injection of histamine or by procedures that release endogenous histamine, which suggests that the transducers are coupled to histamine receptors. Intradermal injection of a large dose of histamine produces intense itch that persists for tens of minutes but only mild pain, a strong indication that itch is not the result of low-level firing in polymodal nociceptors. Instead, itch appears to be mediated by a recently discovered class of C fibers with very slow conduction velocities (0.5 m/s) and physiological properties paralleling the time course of histamine-evoked itch.
Visceral Sensations Represent the Status of Various Internal Organs
Visceral sensations are important physiologically because they drive several types of behavior that are critical for survival, such as respiration, hunger, thirst, sexual arousal, and copulation. After about a minute without breathing, hunger for air, feelings of suffocation, and the need to relieve those sensations become all-consuming behavioral goals. These sensations allow us to hold our breath when needed with the knowledge that an internal sensory signal will tell us when it is no longer safe to do so. Thirst and hunger likewise provide the motivation to drink and eat; they come to dominate our behavior when we have been without water or food for periods that threaten our survival.
Visceral sensations that are linked directly to survival result from both peripheral and central sensors. Sensations associated with the need to breathe, for example, arise from partial pressure of oxygen (PO2) and partial pressure of carbon dioxide (PCO2) sensors in the carotid bodies associated with the carotid arteries and from PCO2 receptors in the respiratory centers of the medulla and hypothalamus (see Chapter 45). Damage to these medullary centers results in a loss of air hunger (Ondine's curse) and often death from failure of automatic breathing during sleep.
Hunger arises from an interaction between signals from hypothalamic chemoreceptors that respond to a variety of molecules in the blood and signals from the gut that indicate the presence or absence of food (see Chapter 49). Thirst results from central mechanisms whose site is uncertain and from peripheral signals from osmoreceptors in the liver and stretch receptors in the cardiopulmonary blood vessels that provide information on blood volume (see Chapter 49).
Nausea, which teaches animals—including us—which foods are unsafe to eat, depends on vagal serotonin receptors in the gut as well as the area postrema in the brain stem. Neurons within the area postrema are able to sense toxins in the blood and cerebrospinal fluid because the area lacks a blood-brain barrier (see Appendix D).
Sensations associated with sexual arousal and copulation, which are essential for survival of the species, arise from low-threshold mechanoreceptors in the genitalia and other body sites. Although the central component is not certain, functional imaging studies and experimental lesion studies suggest that the preoptic area and anterior hypothalamus are important components of arousal (see Chapter 47).