Physiology of Skin Receptors

Cutaneous receptor
A cutaneous receptor is a type of sensory receptor found in the dermis or epidermis. They are a
part of the somatosensory system. Cutaneous receptors include e.g. cutaneous
mechanoreceptors, nociceptors (pain) and thermoreceptors (temperature).

Types
The sensory receptors in the skin are:

 cutaneous mechanoreceptors
o Ruffini's end organ (sustained pressure)
o Meissner's corpuscle (changes in texture, slow vibrations)
o Pacinian corpuscle (deep pressure, fast vibrations)
o Merkel's disc (sustained touch and pressure)
 Thermoreceptor
 Nociceptor
 bulboid corpuscles
 chemoreceptor

Modalities
With the above mentioned receptor types the skin can sense the modalities touch, pressure,
vibration, temperature and pain. The modalities and their receptors are partly overlapping, and
are innervated by different kinds of fiber types.

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Mechanoreceptor
A mechanoreceptor is a sensory receptor that responds to mechanical pressure or distortion.
There are four main types in the glabrous skin of humans: Pacinian corpuscles, Meissner's
corpuscles, Merkel's discs, and Ruffini corpuscles. There are also mechanoreceptors in the hairy
skin, and the hair cells in the cochlea are the most sensitive mechanoreceptors, transducing air
pressure waves into sound.

Mechanism of sensation
Mechanoreceptors are primary neurons that respond to mechanical stimuli by firing action
potentials. Peripheral transduction is believed to occur in the end-organs.

In somatosensory transduction, the afferent neurons transmit the message through synapses in
the dorsal column nuclei, where the second order neurons send the signal to the thalamus and
synapse with the third order neurons in the ventrobasal complex. The third order neurons then
send the signal to the somatosensory cortex.

Types
Cutaneous

Cutaneous mechanoreceptors are located in the skin, like other cutaneous receptors. They are
all innervated by Aβ fibers, except the mechanorecepting free nerve endings, which are
innervated by Aδ fibers. They can be categorized both by morphology, by what kind of
sensation they perceive and by the rate of adaptation. Furthermore, they have different
receptive field.

By morphology

 Ruffini's end organ detects tension deep in the skin.

 Meissner's corpuscle detects changes in texture (vibrations around 50 Hz); adapts
rapidly.
 Pacinian corpuscle detects rapid vibrations (about 200-300 Hz).
 Merkel's disc detects sustained touch and pressure.
 Mechanorecepting Free nerve endings (touch, pressure, stretch)
 Hair follicle receptors are located in hair follicles and sense position changes of hairs.

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By sensation

Cutaneous mechanoreceptors provide the senses of touch, pressure, vibration, proprioception

and others.

 The Slowly Adapting type 1 (SA1) mechanoreceptor, with the Merkel cell end-organ,
underlies the perception of form and roughness on the skin.[4] They have small
receptive fields and produce sustained responses to static stimulation.
 The Slowly Adapting type 2 (SA2) mechanoreceptors respond to skin stretch, but have
not been closely linked to either proprioceptive or mechanoreceptive roles in
perception.[5] They also produce sustained responses to static stimulation, but have
large receptive fields.
 The Rapidly Adapting (RA) mechanoreceptor underlies the perception of flutter[6] and
slip on the skin.[7] They have small receptive fields and produce transient responses to
the onset and offset of stimulation.
 Pacinian receptors underlie the perception of high frequency vibration.[8] They also
produce transient responses, but have large receptive fields.

By rate of adaptation

Cutaneous mechanoreceptors can also be separated into categories based on their rates of
adaptation. When a mechanoreceptor receives a stimulus it begins to fire impulses or action
potentials at an elevated frequency (the stronger the stimulus the higher the frequency). The
cell, however, will soon “adapt” to a constant or static stimulus and the pulses will subside to a
normal rate. Receptors that adapt quickly (i.e. quickly return to a normal pulse rate) are
referred to as ‘’phasic’’. Those receptors that are slow to return to their normal firing rate are
called ‘’tonic’’. Phasic mechanoreceptors are useful in sensing such things as texture, vibrations,
etc; whereas tonic receptors are useful for temperature and proprioception among others.

 Slowly adapting

Slowly adapting mechanoreceptors include Merkel and Ruffini corpuscle end-organs, some free
nerve endings.

o Slowly adapting type I mechanoreceptors have multiple Merkel corpuscle end-

organs.
o Slowly adapting type II mechanoreceptors have single Ruffini corpuscle end-
organs.

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  Intermediate adapting

Some free nerve endings are intermediate adapting.

 Rapidly adapting

Rapidly adapting mechanoreceptors include Meissner corpuscle end-organs, Pacinian corpuscle

end-organs, hair follicle receptors and some free nerve endings.

o Rapidly adapting type I mechanoreceptors have multiple Meissner corpuscle

end-organs.
o Rapidly adapting type II mechanoreceptors (usually called Pacinian) have single
Pacinian corpuscle end-organs.

 Receptive field

Cutaneous mechanoreceptors with small, accurate receptive fields are found in areas needing
accurate taction (e.g. the fingertips). In the fingertips and lips, innervation density of slowly
adapting type I and rapidly adapting type I mechanoreceptors are greatly increased. These two
types of mechanoreceptors have small discrete receptive fields and are thought to underlie
most low threshold use of the fingers in assessing texture, surface slip, and flutter.
Mechanoreceptors found in areas of the body with less tactile acuity tend to have larger
receptive fields.

 Others

Other mechanoreceptors than cutaneous ones include the hair cells, which are sensory
receptors in the vestibular system in the inner ear, where they contribute to the auditory
system and equilibrioception. There are also Juxtacapillary (J) receptors, which respond to
events such as pulmonary edema, pulmonary emboli, pneumonia, and barotrauma.

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The Pacinian Corpuscle
Pacinian corpuscles are pressure receptors. They are located in the skin and also in various
internal organs. Each is connected to a sensory neuron. Because of its relatively large size, a
single Pacinian corpuscle can be isolated and its properties studied. Mechanical pressure of
varying strength and frequency is applied to the corpuscle by the stylus. The electrical activity is
detected by electrodes attached to the preparation.

Deforming the corpuscle creates a generator potential in the sensory neuron arising within it.
This is a graded response: the greater the deformation, the greater the generator potential. If
the generator potential reaches threshold, a volley of action potentials (also called nerve
impulses) are triggered at the first node of Ranvier of the sensory neuron.

Once threshold is reached, the magnitude of the stimulus is encoded in the frequency of
impulses generated in the neuron. So the more massive or rapid the deformation of a single
corpuscle, the higher the frequency of nerve impulses generated in its neuron.

The optimal sensitivity of Pacinian Corpuscle is 250 Hz and this is the frequency range
generated upon finger tips by textures made of features smaller than 200 µms.

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Thermoreceptor
A thermoreceptor is a sensory receptor, or more accurately the receptive portion of a sensory
neuron, that codes absolute and relative changes in temperature, primarily within the
innocuous range. In the mammalian peripheral nervous system warmth receptors are thought
to be unmyelinated C-fibres (low conduction velocity), while those responding to cold have
both C-fibers and thinly myelinated A delta fibers (faster conduction velocity). The adequate
stimulus for a warm receptor is warming, which results in an increase in their action potential
discharge rate. Cooling results in a decrease in warm receptor discharge rate. For cold receptors
their firing rate increases during cooling and decreases during warming. Some cold receptors
also respond with a brief action potential discharge to high temperatures, i.e. typically above
45°C, and this is known as a paradoxical response to heat. The mechanism responsible for this
behavior has not been determined. A special form of thermoreceptor is found in some snakes,
the viper pit organ and this specialized structure is sensitive to energy in the infrared part of the
spectrum.

Location
In mammals, temperature receptors innervate various tissues including the skin (as cutaneous
receptors), cornea and urinary bladder. Neurons from the pre-optic and hypothalamic regions
of the brain that respond to small changes in temperature have also been described, providing
information on core temperature. The hypothalamus is involved in thermoregulation, the
thermoreceptors allowing feed-forward responses to a predicted change in core body
temperature in response to changing environmental conditions.

Warm and cold receptors play a part in sensing innocuous environmental temperature.
Temperatures likely to damage an organism are sensed by sub-categories of nociceptors that
may respond to noxious cold, noxious heat or more than one noxious stimulus modality (i.e.,
they are polymodal). The nerve endings of sensory neurons that respond preferentially to
cooling are found in moderate density in the skin but also occur in relatively high spatial density
in the cornea, tongue, bladder, and facial skin. The speculation is that lingual cold receptors
deliver information that modulates the sense of taste; i.e. some foods taste good when cold,
while others do not.

Structure
Thermoreceptors have been classically described as having 'free' non-specialised endings; the
mechanism of activation in response to temperature changes is not completely understood.

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Function
Cold-sensitive thermoreceptors give rise to the sensations of cooling, cold and freshness. In the
cornea cold receptors are thought to respond with an increase in firing rate to cooling produced
by evaporation of lacrimal fluid 'tears' and thereby to elicit a reflex blink.

Mechanism of transduction
This area of research has recently received considerable attention with the identification and
cloning of the Transient Receptor Potential (TRP) family of proteins. The transduction of
temperature in cold receptors is mediated in part by the TRPM8 channel. This channel passes a
mixed inward cationic (predominantly carried by Na+ ions although the channel is also
permeable to Ca2+) current of a magnitude that is inversely proportional to temperature. The
channel is sensitive over a temperature range spanning about 10-35°C. TRPM8 can also be
activated by the binding of an extracellular ligand. Menthol can activate the TRPM8 channel in
this way. Since the TRPM8 is expressed in neurones whose physiological role is to signal cooling,
menthol applied to various bodily surfaces evokes a sensation of cooling. The feeling of
freshness associated with the activation of cold receptors by menthol, particularly those in
facial areas with axons in the trigeminal (V) nerve, accounts for its use in numerous toiletries
including toothpaste, shaving lotions, facial creams and the like. Another molecular component
of cold transduction is the temperature dependence of so-called leak channels which pass an
outward current carried by potassium ions. Some leak channels derive from the family of two-
pore (2P) domain potassium channels. Amongst the various members of the 2P-domain
channels, some close quite promptly at temperatures less than about 28°C (eg. TRAAK, TREK).
Temperature also modulates the activity of the Na+/K+-ATPase. The Na+/K+-ATPase is a P-type
pump that extrudes 3Na+ ions in exchange for 2K+ ions for each hydrolytic cleavage of ATP. This
results in a net movement of positive charge out of the cell, i.e. a hyperpolarizing current. The
magnitude of this current is proportional to the rate of pump activity. It has been suggested
that it is the constellation of various thermally sensitive proteins together in a neuron that gives
rise to a cold receptor. This emergent property of the neuron is thought to comprise, the
expression of the aforementioned proteins as well as various voltage-sensitive channels
including the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channel and the rapidly
activating and inactivating transient potassium channel (IKA).

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Nociceptor
A nociceptor is a sensory receptor that responds to potentially damaging stimuli by sending
nerve signals to the spinal cord and brain. This process, called nociception, usually causes the
perception of pain.

History
Nociceptors were discovered by Charles Scott Sherrington in 1906. In earlier centuries,
scientists believed that animals were like mechanical devices that transformed the energy of
sensory stimuli into motor responses. Sherrington used many different styles of experiments to
demonstrate that different types of stimulation to a nerve's receptive field led to different
responses. Some intense stimuli trigger reflex withdrawal, autonomic responses and pain. The
specific receptors for these intense stimuli were called nociceptors.

Location
In mammals, nociceptors are sensory neurons that are found in any area of the body that can
sense pain either externally or internally. External examples are in tissues such as skin
(cutaneous nociceptors), cornea and mucosa. Internal nociceptors are in a variety of organs,
such as the muscle, joint, bladder, gut and continuing along the digestive tract. The cell bodies
of these neurons are located in either the dorsal root ganglia or the trigeminal ganglia. The
trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia associate
with the rest of the body. The axons extend into the peripheral nervous system and terminate
in branches to form receptive fields.

Development
Nociceptors develop from neural crest stem cells. The neural crest is responsible for a large part
of early development in vertebrates. More specifically it is responsible for development of the
peripheral nervous system. The neural crest stem cells split off from the neural tube as it closes,
and nociceptors grow from the dorsal part of this neural crest tissue. They form late during
neurogenesis. Earlier forming cells from this region can become non-pain sensing receptors;
either proprioceptors or low-threshold mechanoreceptors. All neurons derived from neural
crest, including embryonic nociceptors, express the TrkA nerve growth factor (NGF). However,
transcription factors that determine the type of nociceptor remain unclear.

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Following sensory neurogenesis, differentiation occurs and two different types of nociceptors
are formed. They are classified as either peptidergic or nonpeptidergic nociceptors. The sets of
receptors express distinct repertoires of ion channels and receptors. With their specialization, it
allows the receptors to innervate different peripheral and central targets. This differentiation
occurs in both perinatal and postnatal periods. The nonpeptidergic nociceptors switch off the
TrkA nerve growth factor and begin expressing Ret. Ret is a transmembrane signaling
component which allows for the expression of another growth factor—glial cell-derived growth
factor (GDNF). This transition is assisted by Runx1 which has proven to be vital in the
development of nonpeptidergic nociceptors. On the contrary, the peptidergic nociceptors
continue to use TrkA and they express a completely different type of growth factor. Currently
there is a lot of research being done to determine more specifically what creates the
differences between nociceptors.

Types and functions

The peripheral terminal of the mature nociceptor is where the noxious stimuli are detected and
transduced into electrical energy. When the electrical energy reaches a threshold value, an
action potential is induced and driven towards the central nervous system (CNS). This leads to
the train of events that allows for the conscious awareness of pain. The sensory specificity of
nociceptors is established by the high threshold only to particular features of stimuli. Only when
the high threshold has been reached by either chemical, thermal, or mechanical environments
are the nociceptors triggered. The majority of nociceptors are classified by which of the
environmental modalities they respond to. Some nociceptors respond to more than one of
these modalities and are consequently designated polymodal. Other nociceptors respond to
none of these modalities (although they may respond to stimulation under conditions of
inflammation) and are referred to as sleeping or silent nociceptors.

Nociceptors have two different types of axons. The first are the Aδ fiber axons. They are
myelinated and can allow an action potential to travel at a rate of about 20 meters/second
towards the CNS. The other type is the more slowly conducting C fiber axons. These only
conduct at speeds of around 2 meters/second. This is due to the light or non-myelination of the
axon. As a result, pain comes in two phases. The first phase is mediated by the fast-conducting
Aδ fibers and the second part due to (Polymodal) C fibers. The pain associated with the Aδ
fibers can be associated to an initial extremely sharp pain. The second phase is a more
prolonged and slightly less intense feeling of pain as a result from the damage. If there is
massive or prolonged input to a C fiber there is progressive build up in the spinal cord dorsal
horn. This phenomenon is similar to tetanus in muscles but is called wind-up. If wind-up occurs
there is a probability of increased sensitivity to pain.

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Thermal
Thermal nociceptors are activated by noxious heat or cold at various temperatures. There are
specific nociceptor transducers that are responsible for how and if the specific nerve ending
responds to the thermal stimulus. The first to be discovered was TRPV1, and it has a threshold
that coincides with the heat pain temperature of 42°C. Other temperature in the warm-hot
range is mediated by more than one TRP channel. Each of these channels express a particular C-
terminal domain that corresponds to the warm-hot sensitivity. The interactions between all
these channels and how the temperature level is determined to be above the pain threshold
are unknown at this time. The cool stimuli are sensed by TRPM8 channels. Its C-terminal
domain differs from the heat sensitive TRPs. Although this channel corresponds to cool stimuli,
it is still unknown whether it also contributes in the detection of intense cold. An interesting
finding related to cold stimuli is that tactile sensibility and motor function deteriorate while
pain perception persists.

Mechanical
Mechanical nociceptors respond to excess pressure or mechanical deformation. They also
respond to incisions that break the skin surface. The reaction to the stimulus is processed as
pain by the cortex, just like chemical and thermal responses. These mechanical nociceptors
frequently have polymodal characteristics. So it is possible that some of the transducers for
thermal stimuli are the same for mechanical stimuli. The same is true for chemical stimuli, since
TRPA1 appears to detect both mechanical and chemical changes.

Chemical
Chemical nociceptors have TRP channels that respond to a wide variety of spices commonly
used in cooking. The one that sees the most response and is very widely tested is Capsaicin.
Other chemical stimulants are environmental irritants like acrolein, a World War I chemical
weapon and a component of cigarette smoke. Besides from these external stimulants, chemical
nociceptors have the capacity to detect endogenous ligands, and certain fatty acid amines that
arise from changes in internal tissues. Like in thermal nociceptors, TRPV1 can detect chemicals
like capsaicin and spider toxins.

Sleeping/silent
Although each nociceptor can have a variety of possible threshold levels, some do not respond
at all to chemical, thermal or mechanical stimuli unless injury actually has occurred. These are
typically referred to as silent or sleeping nociceptors since their response comes only on the
onset of inflammation to the surrounding tissue.

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Pathway
Afferent nociceptive fibers (those that send information to, rather than from the brain) travel
back to the spinal cord where they form synapses in its dorsal horn. This nociceptive fiber
(located in the periphery) is a first order neuron. The cells in the dorsal horn are divided into
physiologically distinct layers called laminae. Different fiber types form synapses in different
layers, and use either glutamate or substance P as the neurotransmitter. Aδ fibers form
synapses in laminae I and V, C fibers connect with neurons in lamina II, Aβ fibers connect with
lamina I, III, & V. After reaching the specific lamina within the spinal cord, the first order
nociceptive project to second order neurons and cross the midline.

The second order neurons then send their information via two pathways to the thalamus: the
dorsal column medial-lemniscal system and the anterolateral system. The first is reserved more
for regular non-painful sensation, while the lateral is reserved for pain sensation. Upon
reaching the thalamus, the information is processed in the ventral posterior nucleus and sent to
the cerebral cortex in the brain. As there is an ascending pathway to the brain that initiates the
conscious realization of pain, there also is a descending pathway which modulates pain sensory.
The brain can request the release of specific hormones or chemicals that can have analgesic
effects which can reduce or inhibit pain sensation. The area of the brain that stimulates the
release of these hormones is the hypothalamus.

This effect of descending inhibition can be shown by electrically stimulating the periaqueductal
grey area of the midbrain. The periaqueductal grey in turn projects to other areas involved in
pain regulation, such as the nucleus raphe magnus (which also receives similar afferents from
the nucleus reticularis paragigantocellularis (NPG). In turn the nucleus raphe magnus projects
to the substantia gelatinosa region of the dorsal horn and mediates the sensation of
spinothalamic inputs. The periaqueductal grey also contains opioid receptors which explains
one of the mechanisms by which opioids such as morphine and diacetylmorphine exhibit an
analgesic effect.

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Sensitivity
Nociceptor neuron sensitivity is modulated by a large variety of mediators in the extracellular
space.[8] Peripheral sensitization represents a form of functional plasticity of the nociceptor.
The nociceptor can change from being simply a noxious stimulus detector to a detector of non-
noxious stimuli. The result is that low intensity stimuli from regular activity, initiates a painful
sensation. This is commonly known as hyperalgesia. Inflammation is one common cause that
results in the sensitization of nociceptors. Normally hyperalgesia ceases when inflammation
goes down, however, sometimes genetic defects and/or repeated injury can result in allodynia:
a completely non-noxious stimulus like light touch causes extreme pain. Allodynia can also be
caused when a nociceptor is damaged in the peripheral nerves. This can result in
deafferentation, which means the development of different central processes from the
surviving afferent nerve. With this situation, surviving dorsal root axons of the nociceptors can
make contact with the spinal cord, thus changing the normal input

Nociceptors in non-mammalian animals

Nociception has been documented in non-mammalian animals, including fish and a wide range
of invertebrates, including leeches, nematode worms, sea slugs, and fruit flies. Although these
neurons may have different pathways and relationships to the central nervous system than
mammalian nociceptors, nociceptive neurons in non-mammals often fire in response to similar
stimuli as mammals, such as high temperature (40 degrees C or more), low pH, capsaicin, and
tissue damage.

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Bulboid corpuscle

The bulboid corpuscles (end-bulbs of Krause) are cutaneous receptors in the human body.

The end-bulbs of Krause were named after German anatomist Wilhelm Krause (1833-1910).

Function
They have the ability to detect low-frequency vibration.

Structure
They are minute cylindrical or oval bodies, consisting of a capsule formed by the expansion of
the connective-tissue sheath of a medullated fiber, and containing a soft semifluid core in which
the axis-cylinder terminates either in a bulbous extremity or in a coiled-up plexiform mass.

Location
End-bulbs are found in the conjunctiva of the eye (where they are spheroidal in shape in
humans, but cylindrical in most other animals), in the mucous membrane of the lips and
tongue, and in the epineurium of nerve trunks.

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They are also found in the penis and the clitoris and have received the name of genital
corpuscles; in these situations they have a mulberry-like appearance, being constricted by
connective-tissue septa into from two to six knob-like masses.

In the synovial membranes of certain joints, e. g., those of the fingers, rounded or oval end-
bulbs occur, and are designated articular end-bulbs.

Meissner's corpuscle
Meissner's corpuscles (or tactile corpuscles) are a type of mechanoreceptor. They are a type of
nerve ending in the skin that is responsible for sensitivity to light touch. In particular, they have
highest sensitivity (lowest threshold) when sensing vibrations lower than 50 Hertz. They are
rapidly adaptive receptors.

Location
They are distributed on various areas of the skin, but concentrated in areas especially sensitive
to light touch, such as the fingers, lips and nipples. Sources differ as to whether they are
present in the male prepuce (foreskin): while Winkelmann (1956) reported that they were not
present in the foreskin of newborn males, Taylor (1996) noted their presence, and (1999)
reported "Most of the encapsulated receptors of the foreskin are Meissner corpuscles, as they
contact the epithelial basement membrane." Winkelmann discussed the conflicting literature
on the subject, noting that Dogiel, Ohmori, and Bazett et al. reported the presence of
Meissner's corpuscles in the foreskin, and that their descriptions of the structures concerned
did not agree. Haiyang et al. (2005) found Meissner's corpuscles in some, but not all, foreskins;
their density did not differ between specimens taken from phimosis and abundant prepuce
groups. Dong et al. (2007) reported that the quantity of Meissner's corpuscles on the fused
smooth mucosa of the foreskin decline with age, but not on the ridged band. They are primarily
located just beneath the epidermis within the dermal papillae.

Structure
Meissner's corpuscles are encapsulated unmyelinated nerve endings, which consist of flattened
supportive cells arranged as horizontal lamellae surrounded by a connective tissue capsule. The
corpuscle is between 30-140 μm in length and 40-60 μm in diameter.

A single nerve fiber meanders between the lamellae and throughout the corpuscle.

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Function
Any physical deformation in the corpuscle will cause an action potential in the nerve. Since they
are rapidly adapting or phasic, the action potentials generated quickly decrease and eventually
cease. (This is the reason one stops "feeling" one's clothes.)

If the stimulus is removed, the corpuscle regains its shape and while doing so (ie: while
physically reforming) causes another volley of action potentials to be generated.

Because of their superficial location in the dermis, these corpuscles are particularly sensitive to
touch and vibrations, but for the same reasons, they are limited in their detection because they
can only signal that something is touching the skin.

Comparison with other receptors

Feelings of deep pressure (from a poke, for instance) are generated from Pacinian corpuscles
(the only other type of phasic tactile mechanoreceptor), which are located deeper in the
dermis, and some free nerve endings.

Also, Meissner's corpuscles do not detect pain; this is signalled exclusively by free nerve
endings.

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 References
1. http://www.exploringnature.org/db/detail.php?dbID=25&detID=47
2. http://en.wikipedia.org/wiki/Cutaneous_mechanoreceptors#Cutaneous
3. http://en.wikipedia.org/wiki/Cutaneous_receptor
4. http://www.medicalook.com/human_anatomy/organs/Lamellated_corpuscles.html
5. http://en.wikipedia.org/wiki/Thermoreceptor
6. http://en.wikipedia.org/wiki/Nociceptor
7. http://en.wikipedia.org/wiki/Bulboid_corpuscles
8. http://en.wikipedia.org/wiki/Meissner_corpuscle_end-organ

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