Itch

Itch (Latin: pruritus) is an unpleasant sensation that evokes the desire or reflex to scratch. Itch has many similarities to pain and both are unpleasant sensory experiences but their behavioral response patterns are different. Pain creates a reflex withdrawal while itch leads to a scratch reflex. Unmyelinated nerve fibers for itch and pain both originate in the skin, however information for them is conveyed centrally in two distinct systems that both use the same peripheral nerve bundle and spinothalamic tract.

Historically, the sensations of itch and pain have not been considered to be independent of each other until recently where it was found that itch has several features in common with pain but exhibits notable differences. The physiological mechanisms of itch are currently poorly understood and this is mainly due to the lack of animal models of itch. Pruritic stimuli mostly create the same reactions as noxious stimuli in experimental animals, but humans are capable of discerning the distinct features of itch and pain. Therefore human studies have provided most of the information regarding the processing of pruritic stimuli.

Mechanism
Itch can originate in the peripheral nervous system (dermal or neuropathic) or in the central nervous system (neuropathic, neurogenic, or psychogenic).

Dermal/pruritoceptive
Itch originating in the skin is considered pruritoceptive and can be induced by a variety of stimuli, including mechanical, chemical, thermal, and electrical stimulation. The primary afferent neurons responsible for histamine induced itch are unmyelinated C-fibers. In human C-fiber nociceptors, two major classes exist: mechano-responsive nociceptors and mechano-insensitive nociceptors. Mechano-responsive nociceptors have been shown in studies to respond to mostly pain and mechano-insensitive receptors respond mostly to itch induced by histamine. However it does not explain mechanically induced itch or when itch is produced without a flare reaction which involves no histamine. Therefore it is possible that pruritoceptive nerve fibers have different classes of fibers, which is unclear in current research.

Studies have been done to show that itch receptors are only found on the top two skin layers, the epidermis and the epidermal/dermal transition layers. Shelley and Arthur had verified the depth by injecting individual itch powder spicules (Mucuna pruriens) and found that maximal sensitivity was found at the basal cell layer or the innermost layer of the epidermis. Surgical removal of those skin layers removed the ability for a patient to perceive itch. Itch is never felt in muscle, joints, or inner organs, which show that deep tissue does not contain itch signaling apparatuses.

Sensitivity to pruritic stimuli is not even across the skin and has a random spot distribution with similar density to that of pain. The same substances that elicit itch upon intracutaneous injection (injection within the skin) elicit only pain when injected subcutaneously (beneath the skin). Itch is readily abolished in skin areas treated with nociceptor excitotoxin capsaicin but remains unchanged in skin areas which were rendered touch-insensitive by pretreatment with saponins, an anti-inflammatory agent. Although experimentally induced itch can still be perceived under a complete A-fiber conduction block, it is significantly diminished. Overall, itch sensation is mediated by A-delta and C nociceptors located in the uppermost layer of the skin.

Neuropathic
Neuropathic itch can originate at any point along the afferent pathway as a result of damage of the nervous system. They could include diseases or disorders in the central nervous system or peripheral nervous system. Examples of neuropathic itch in origin are nostalgia paresthetica, brachioradial pruritis, brain tumors, multiple sclerosis, peripheral neuropathy, and nerve irritation.

Neurogenic
Neurogenic itch, which is itch induced centrally but with no neural damage, is often associated with increased accumulation of endogenous opioids and possibly synthetic opioids.

Psychogenic
Itch is also associated with some psychiatric disorders such as delusions of parasitosis or related obsessive-compulsive disorders, for example neurotic scratching.

Pain inhibits itch
The sensation of itch can be reduced by many painful sensations. Many studies done in the last decade have shown that itch can be inhibited by many other forms of painful stimuli, such as noxious heat, physical rubbing/scratching, noxious chemicals, and electric shock. Any stimulus that causes pain will inhibit itching.

The inhibition of itch by painful stimuli, including heat, physical stimulus, and chemical stimulus, has been shown experimentally. In an article written by Louise Ward and others, they studied the effects of noxious and non-noxious counterstimuli, such as heat, physical vibration, or chemical stimulation on skin, in healthy adults after they had experimentally induced itch (transdermal iontophoresis of histamine) and pain (with topical mustard oil) in their skin. They found that when they induced non-noxious counterstimuli, the reduction of pain and itch was reduced only for up to 20 seconds. However when they induced noxious counterstimuli, there was a significant inhibition of itch for an extended period of time but no inhibition of pain. In addition, it was found that brief noxious stimuli created an anti-itch state for more than 30 minutes. These findings show that itch is not a subliminal form of pain and that noxious counterstimulus is likely to act through a central instead of a peripheral mechanism.

Painful electrical stimulation reduced histamine-induced itch for several hours at a distance up to 10 cm from the stimulated site, which suggests a central mode of action. A new method had been recently found, by Hans-Jorgen Nilsson and others, that is able to relieve itch without damaging the skin called cutaneous field stimulation (CFS). CFS consists of a flexible rubber plate with 16 needle-like electrodes placed regularly at 2-centimeter intervals in a 4 by 4 matrix used to electrically stimulate nerve fibers in the surface of the skin. The electrodes were stimulated continuously at 4 Hertz per electrode, pulse duration of 1 millisecond, intensity 0.4-0.8 milliamperes, and for 25 minutes. CFS resulted in a pricking and burning sensation that usually faded away very quickly. The burning sensation was still present during a selective block of impulse conduction of A-fibers in myelinated fibers indicating that nociceptive C-fibers are activated by CFS. In addition, a flare reaction had been noted to develop around the CFS electrodes which indicate activation of axon reflexes in nociceptive C-fibers. Itch, which was induced by transdermal iontophoresis of histamine, was inhibited within the skin area treated with CFS, and it was reduced 10 cm distally to a significant amount. CFS proves to offer a new method of combating itch by using painful electrical stimulation as it creates a long lasting inhibitory effect, does not create any significant skin injuries, and is simple to manage. It is able to activate powerful itch inhibitory mechanisms possibly routed through central mechanisms, which could normally be activated by scratching of the skin.

A study done by Gil Yosipovitch, Katharine Fast, and Jeffrey Bernhard showed that noxious heat and scratching was able to inhibit or decrease itch induced by transdermal iontophoresis of histamine and most interestingly, decrease skin blood flow. Twenty-one healthy volunteers participated in their study. Baseline measurements of skin blood flow were obtained on the flexor part of the forearm and then compared with skin blood flow after various stimuli. Then transdermal iontophoresis of histamine was performed and tested with various stimuli. It is well known that skin blood flow is significantly increased during mechanical scratching, warming, and noxious heat. However it is quite interesting that this study is the first to examine the changes of blood flow by stimuli during iontophoresis of histamine and how itch is perceived in those conditions. Its examination provided an unexpected result that noxious heat and scratching has an inhibitory effect.

A negative correlation was found between pain sensitivity and itch sensitivity. In a study done by Amanda Green and others, they aimed to determine itch-related genetic factors, and establish a more useful animal model for itch. They looked at 11 different inbred mouse strains and compared their scratching behavior in response to two itch inducing agents, histamine and chloroquine. Every strain revealed an inverted-U shape dose response relationship from chloroquine, indicating that moderate dosages produced more scratching than at higher dosages. An explanation is that higher dosage produces more pain and the presence of pain inhibits itch thereby lowering the amount of overall scratching. Another notable result was that histamine induced scratching occurred in female mice on average 23% more than males. Finally, it was found that mice having strains sensitive to pain were resistant to itch and vice versa.

Peripheral sensitization
Inflammatory mediators such as bradykinin, serotonin (5-HT) and prostaglandins, released during a painful or pruritic inflammatory condition not only activates pruriceptors but also causes acute sensitization of the nociceptors. In addition, expression of neuro growth factors (NGF) can cause structural changes in of nociceptors such as sprouting. NGF is high in injured or inflamed tissue. Increased NGF is also found in atopic dermatitis, a hereditary and non-contagious skin disease with chronic inflammation. NGF is known to up-regulate neuropeptides, especially substance P. Substance P has been found to have an important role in inducing pain however there is no confirmation that substance P directly causes acute sensitization. Instead substance P may contribute to itch by increasing neuronal sensitization and may the affect release of mast cells, which contain many granules rich in histamine, during long-term interaction.

Central sensitization
Noxious input to the spinal cord is known to produce central sensitization, which consists of allodynia, exaggeration of pain, and punctuate hyperalgesia, extreme sensitivity to pain. Two types of mechanical hyperalgesia can occur: 1) touch that is normally painless in the uninjured surroundings of a cut or tear can trigger painful sensations (touch-evoked hyperalgesia), and 2) a slightly painful pin prick stimulation is perceived as more painful around a focused area of inflammation (punctuate hyperalgesia). Touch-evoked hyperalgesia requires continuous firing of primary afferent nociceptors, and punctuate hyperalgesia does not require continuous firing which means it can persist for hours after a trauma and can be stronger than normally experienced. In addition, it was found that patients with neuropathic pain, histamine ionophoresis resulted in a sensation of burning pain rather than itch, which would be induced in normal healthy patients. This shows that there is spinal hypersensitivity to C-fiber input in chronic pain.

Causes
The feeling of itchiness can be caused by a movement of hair or the release of a chemical (histamine) from cells under the skin. Itchiness is regarded as protective, as it helps creatures remove parasites that land on their skin.

Itching can be caused by: Chloroquine - by stimulating mu opiate receptors (MOR) and inhibiting Kappa opiate Receptors (KOR)
 * Xerosis. This is the most common cause, frequently seen in winters.  Associated with older age, frequent bathing in hot showers or baths, and high temperature and low humidity environments.
 * Skin conditions (such as psoriasis, eczema, sunburn, athlete's foot, hidradenitis suppurativa and many others). Most are of an inflammatory nature.
 * Insect bites, such as those from mosquitos or chiggers.
 * Allergic reactions to contact with specific chemicals, such as Urushiol from Poison Ivy or Poison Oak.
 * Hodgkin's disease
 * Jaundice (bilirubin is a skin irritant at high concentrations)
 * Polycythemia, which can cause generalized itching due to increased histamine
 * Scabies or infection with lice or worms
 * Thyroid illness
 * hyperparathyroidism
 * Shaving, which may irritate the skin
 * Uraemia
 * Diabetes Mellitus
 * Dandruff (an unusually large amount of flaking is associated with this sensation)
 * Iron deficiency anemia
 * Parasitic infections
 * Psychiatric
 * Medication:
 * Allergy - (due to reaction of an individual's immune system to certain chemical compounds)
 * Photodermatitis – (sun)light reacts with chemicals in the skin, leading to the formation of irritant metabolites
 * Directly (e.g. morphine and other opiates)
 * Cholestasis
 * Related to pregnancy:
 * Pruritic Urticarial Papules and Plaques of Pregnancy (PUPPP)
 * Gestational pemphigoid

Treatment
A variety of over-the-counter and prescription anti-itch drugs are available. Some plant products have been found to be effective anti-pruritics, others not. Non-chemical remedies include cooling, warming, soft stimulation.

Crotamiton (trade name Eurax) is an antipruritic agent available as a cream or lotion often used to treat scabies. Its mechanism of action remains unknown.

Sometimes scratching relieves isolated itches, hence the existence of devices such as the back scratcher. Often, however, scratching can intensify itching and even cause further damage to the skin, dubbed the "itch-scratch-itch cycle".

The mainstay of therapy for dry skin is maintaining adequate skin moisture and topical emollients.

Sensations associated with scratching
Pain and itch have very different behavioral response patterns. Pain evokes a withdrawal reflex which leads to retraction and therefore a reaction trying to protect an endangered part of the body. Itch creates a scratching reflex which draws one to the affected skin site. For example, responding to a local itch sensation is an effective way to remove insects on the skin. Scratching has traditionally been regarded as a way to relieve oneself by reducing the annoying itch sensation. However there are hedonic aspects of scratching as one would find noxious scratching highly pleasurable. This can be problematic with chronic itch patients, such as ones with atopic dermatitis, who may scratch affected spots until it no longer produces a pleasant or painful sensation instead of when the itch sensation disappears. It has been hypothesized that motivational aspects of scratching include the frontal brain areas of reward and decision making. These aspects might therefore contribute to the compulsive nature of itch and scratching.

Contagious itch
Events of “contagious itch” are very common occurrences. Even a discussion on the topic of itch can give one the desire to scratch. Itch is likely to be more than a localized phenomenon in the place we scratch. Results from a recent study showed that itching and scratching were induced purely by visual stimuli in a public lecture on itching. There is currently little detailed data on central activation for contagious itching but it is hypothesized that a human mirror neuron system exists in which we imitate certain motor actions when we view others performing the same action. A similar phenomenon in which mirror neurons are used to explain the cause is contagious yawning.