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DERMATOLOGIC THERAPY

ISSN 1396-0296

Blackwell Publishing, Ltd.

Neuroanatomy and neurophysiology of itch

OANNA

ALLENGREN

Department of Dermatology, Clinical Sciences, University Hospital, Lund, Sweden

ABSTRACT:

The specific pathway of “pure,” histaminergic itch is traced from the mechano-insensitive nerve fibers in the skin to their central cortical projections. Neuropathic itch created at different levels of this anatomical pathway is reviewed. In this review the present author discusses damage to pruri- toceptors in the skin, entrapment syndromes, damage to spinal ganglia, nerve root impingement, injury of the spinal cord, and cerebral damage in the distribution of the middle cerebral artery, capsula interna, or thalamus. Itch in inflamed skin resulting from interactions between nerve transmitters and other mediators of inflammation is described.

KEYWORDS:

capsaicin, histamine, itch, neuropathic, neuropeptides, pruritus

Introduction

Itch has tormented animals and humans for thou- sands of years, especially when infestations were common, caused by poor hygiene and crowded living. It is often the main symptom of skin disease and a common reason for consulting a dermatolo- gist. Itch-alleviating therapies were practiced long before dermatology achieved the status of a medical discipline.

For a long time itch was regarded as a weak variant of pain, although it can only be elicited in the skin or mucous membranes. In 1927, Lewis proposed that histamine, discovered in 1910, causes itching in inflammatory skin disease (1). Another milestone was the pioneering work of Shelly and Arthur in the 1950s; they used spicula of the fruit of mucuna pruriens (cowhage) to show where in the skin the itch is most easily elicited (itch points) (2). They found that inserting the spicula in the dermo-epidermal juncture area induced the strongest itch. Winkelmann showed this to be the location the location of sensory unmyelinated nerve fibers in the skin (3). In mid 1960s Melzak and Wall proposed a gate theory showing how stimulation of pain inhibits itch (4). Experiments

in the beginning of 1980 showed that increasing the intensity of itch induced a stronger itch but no pain (5). This led to the conclusion that itch and pain are separate sensations and that they are transmitted along different pathways. This division promoted more research into itch, which for a long time had been in the shadow of pain, a big brother with a massive annual health bill.

Researchers started looking for “itch receptors” in the periphery and for an “itch center” in the cortex. Although such single entities have not been defined, considerable progress has been made on classifying different forms of itch and on under- standing the underlying mechanisms. In this review the present author follows the neuronal pathway for histamine-induced itch. Cutaneous reactions induced by endogenous pruritogenic mediators and their response to common drugs such as anti- histamines, local anesthetics, indomethacin, and capsaicin are described. Neuropathic itch at dif- ferent levels of the neuronal pathway is described.

The anatomical framework for itch conduction

A neuronal pathway of itch described in this section has been elucidated using histamine as a model for “pure itch.”

Address correspondence and reprint requests to: Joanna Wallengren, MD, PhD, Department of Dermatology, University Hospital, SE-221 85 Lund, Sweden, or email: [email protected].

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Cutaneous nerve fibers conducting itch

Sensory neurons or primary afferent neurons have a unipolar cell body located in the dorsal root ganglia of spinal nerves or in the sensory ganglia of cranial nerves. The axons of neurons that con- duct itch are unmyelinated C fibers that end in the skin at the dermo-epidermal junction, some- times penetrating into the epidermis as free endings. The sensory nerve fibers are mainly peptidergic, with substance P (SP) and calcitonin gene-related peptide (CGRP) as main transmitters (6). Recently, Schmelz and colleagues have used iontophoresis of histamine to show that the C fibers that convey itch comprise about 5% of the afferent C fibers in human skin. Itch-mediating C fibers have slow conduction velocities (0.5 m/s) and large innervation territories (a diameter of 85 mm on the lower leg) compared to polymodal C fibers (7). They respond to thermal stimuli but are insensitive to mechanical stimuli.

Pruritogenic agents or physical factors like thermal stimuli will activate C fibers and lead to the release of transmitters in the skin through an axon reflex (neurogenic inflammation, see succeeding discussion). The depletion of nerve transmitters in the peripheral afferents will stimulate synthesis of new nerve transmitters in the cell bodies of the spinal ganglia (8). The orthodromic nerve trans- mission of sensory C fibers will be conducted through the peripheral processes of the spinal nerves to the spinal ganglia and from there through the central processes of the spinal nerves to the dorsal root of the spinal cord (FIG. 1).

Spinal processing of itch

Most of the nociceptive afferents terminate in the superficial region of the dorsal horn. In experi- ments on rat, intracutaneous administration of histamine, nicotine, and capsaicin, as well as topical application of mustard oil and noxious heat resulted in activation of most superficial dorsal horn neurons (9).

Recently, neurons selectively sensitive to hista- mine “itch-specific neurons” have been identified in cat (10). Mechano- and heat-insensitive neu- rons were identified using antidromic stimulation from thalamus and a collision of antidromic and orthodromic impulses. Later these neurons were tested with histamine applied iontophoretically to the skin. Neurons sensitive to histamine were found to be located in the most superficial part of the dorsal horn lamina I spinothalamic tract (lamina I SST). These neurons cross over the spinal

cord to the contralateral side and their projections will terminate in the lateral part of thalamus. These neurons have been shown to lack ongoing dis- charge (common in pain conduction neurons) and to have slow central conduction velocities (10).

Spino-thalamico-cortal transmission of itch

Primates seem to have a direct pathway from lamina I spinothalamic tract neurons through midbrain to two sites in the thalamus: the ventral medial nucleus and the medial dorsal nucleus (9). The role of thalamus in the emotional processing pain is well known, whereas data diverges con- cerning its role in the modulation of itch.

Experiments using positron emission tomography (PET) regional cerebral blood flow measurements in response to histamine prick test provocation by Drzezga et al. did not show any involvement of the thalamus, whereas similar experiments by Mochizuki et al. on histamine applied by iontophoresis demon- strated activation of the thalamus (11,12).

FIG. 1. Diagram of the course and termination of pruritoceptive information. Itch is conducted by intraepithelial mechano-insensitive nerve fibers ascending to the lamina I in the dorsal horn of the spinal cord. The lamina I spinothalamic tract neurons cross over to the contralateral side and ascend to the thalamus. Neuronal projections from the ventral medial nucleus in the thalamus terminate in the sensorimotor cortex, whereas neurons from the medial dorsal nucleus in the thalamus terminate in the cingulate cortex.

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However, studies using the PET technique have shown that several cortical areas such as the frontal, parietal and cingulated cortex are involved in the processing of itch (11–13). Two main pathways from the thalamus to the cortex may be distinguished (9). Neuronal projections from the ventral medial nucleus in the thalamus terminate in area 3a in sensorimotor cortex, whereas neurons from the medial dorsal nucleus in the thalamus terminate in the anterior cingulate cortex (9). Both these cortical areas have been found to be activated when tracing histamine-induced itch and scratching (11–13). Involvement of the motor cortex explains the urge to scratch contingent on the perception of unpleasant itch. Scratching, in fact, has for a long time been recognized as the most reliable mea- surement of itch (14). Activation of the anterior cingulate cortex, a relay for emotional processing of an array of feelings, romantic love included, explains the affective component of itch (15). A schematic route of itch transmission is shown in FIG. 1.

Cutaneous elicitation of itch

The C-type primary afferent fibers that conduct itch are not only sensitive to neurotransmitters but also to histamine and to other inflammatory mediators (13).

Pruritoceptive nerve fibers and their transmitters

Many nerve transmitters are involved in the conduction of itch. Several neurotransmitters are colocalized and may be switched several times on the way from the skin up to the cortex (16). Like all neuropeptides, most transmitters occur both in the neurons of the peripheral and the central nervous system. Serotonin and histamine occur in cellular structures in the skin but act as nerve transmitters in the neurons of the central nervous system. The C fibers present in the epidermis and papillary dermis are peptidergic, with tachykinins SP and neurokinin A (NKA), and calcitonin gene-related peptide (CGRP) as main transmitters (FIG. 2A) (6).

Substance P.

Substance P, consisting of 11 amino acid residues, is encoded by the same gene as NKA, consisting of 10 amino acid residues (17). Generally, SP-immunoreactive nerve fibres are few or moderate in number, except for instance in the skin of fingertips, where they are numerous.

SP-containing nerve fibers are also known to form a network around sweat glands and blood vessels (6). Activation of C fibers leads to release of transmitters in the skin through an axon reflex, resulting in an inflammatory response called neurogenic inflammation (FIG. 3). Hagermark and Fjellner have studied itch induced by several neuro- peptides; including SP and vasoactive intestinal peptide (VIP), and found that they produce flare, wheal, and itch (FIG. 3) (18). SP-evoked flare is dependent upon an axon reflex, as pretreatment of the skin with lidocaine greatly diminishes the response (19). SP flare is also partly inhibited by indomethacin, blocking synthesis of prostaglan- din, suggesting an interaction between these mediators (20). The flare response to SP, a model for neurogenic inflammation, has been shown to depend on several physiological factors. There is a regional variation of the flare response, which is most prominent on the thorax and less so at more distal locations (20). The flare response dimin- ishes with increasing age and in conditions of physical stress, and its magnitude varies with the time of day, being greater at night (21). The deple- tion of histamine from dermal mast cells by com- pound 48/80 greatly reduces the flare response to SP, suggesting flare to be dependent on histamine (18,19). There is also evidence that histamine H3 receptors are located on peripheral endings of SP nerve fibers (22). Close contacts between mast cells and nerve fibers have been demonstrated (23 –25). Tachykinin receptors are of three sub- types: NK1, NK2, and NK3, and SP mainly acti- vates the NK1 receptor (17). Two SP antagonists, spantide I and spantide II, have been shown to

FIG. 2. Skin from the upper arm of a patient with brachioradial pruritus. (A) Calcitonin gene-related peptide, CGRP-immunoreactive nerve fibers scattered beneath and in the epidermis. (B) Vanilloid receptor VR1-immunoreactive, kite-like structures beneath the epidermis.

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have reduced type I and type IV allergic reactions (26,27)

Calcitonin gene-related peptide.

Calcitonin gene- related peptide (CGRP) is a 37-amino acid peptide that is encoded by the same gene that codes for calcitonin (28). CGRP is the most abundant of all neuropeptides in human skin and is often found to be colocalized with SP (FIG. 2A) (6). In human skin, CGRP induces slowly developing local red- dening (duration of several hours) but no itch (personal experience) (19). The erythema does not seem to be mediated by mast cell histamine or by C-fiber tachykinins, as it is not suppressed by pretreatment with either H1 receptor antagonist, mepyramine, mast cell histamine liberator, com- pound 48/80, or by lidocaine treatment. These findings are in accordance with the finding that CGRP does not induce activation of mast cells and release of histamine (29). The long-lasting and widespread vascular effects of CGRP may reflect a gradual diffusion of the peptide, which conceiv- ably exerts direct effects on blood vessels. CGRP is considered the main mediator of sensory nerve

fibers, being the main mediator of capsaicin-induced erythema in human skin (30). If CGRP is injected intracutaneously together with SP, the duration of the response will shorten (31). Based on the dif- ferential biological activities of various CGRP ana- logs, the CGRP receptors have been classified into CGRP1 and CGRP2 (28). CGRP-antagonist, CGRP/ 8-37/, with affinity for CGRP-1 receptor shown to have dual activity (depending on concentration) on allergic contact dermatitis (32).

Capsaicin as a pharmacological tool

Capsaicin is the active substance in chili peppers and is responsible for their burning taste. Other spicy plants (ginger, black pepper, etc.) also con- tain similar agents, but capsaicin is the most potent and most thoroughly studied. Capsaicin is a highly potent burning substance that selectively stimulates nociceptives and causes release of neuropeptides from afferent temperature-sensitive neurons, both peripherally and within the spinal cord (33). Repeated cutaneous administration of capsaicin abolishes the flare response to SP,

FIG. 3. Schematic illustration of main mediators of neurogenic inflammation. When the thin intraepidermal nerve fibers become activated, the impulse flow is propagated to the central nervous system. Some of the impulses spread to adjacent branches of the nerve in a retrograde direction through an axon reflex. Nerve transmitters are released in the skin and act as inflammatory mediators. SP induces a wheal-and-flare reaction, whereas CGRP induces a persistent erythema with pseudopodia resembling the one of prostaglandin PGE2. SP stimulates mast cells to degranulate and the released histamine stimulates blood vessels and new neurons to release nerve transmitters. The reaction is potentiated by other mediators, such as bradykinin, cytokines, and serotonin released from the inflammatory cells. This cascade of events is dependent on the density of nerve fibers, on the occurrence of mast cells, and on the concentration of inflammatory mediators.

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reflecting release of SP and impairment of the axon reflex (20,34). The flare reaction recovers after about 8 weeks (28). Capsaicin-evoked flare response can be inhibited by lignocaine and indomethacin (21). Systemic, subcutaneous admin- istration of capsaicin in laboratory animals depletes neuropeptides like CGRP, and induces skin ulcers (35).

Recently the capsaicin receptor has been cloned and is now named transient receptor vanilloid 1 ( TRPV1) (33). Expression of heat- activated vanilloid receptor, VR1, binding capsaicin, has been found not only in cutaneous sensory nerves but also in mast cells and epithelial cells (FIG. 2B) (36,37). The vanilloid receptor belongs to the TRP family of excitatory ion channels. Another member of this family has been described recently, namely the cold- and menthol-sensitive receptor, CMR1 (38). CMR1 and VR1 have been shown to coexist sometimes in the same primary afferent neurons and promote to thermo-sensations in a wide range of temperatures 8 –28

C and > 50

C, respectively (38). These findings explain why heating and cooling influence perception of itch.

Neuropeptides in inflammatory and pruritic skin disease

Using radioimmunoassay, high levels of SP, somatostatin, VIP, CGRP, and neuropeptide Y (NPY) were found in spontaneous blisters from inflam- matory skin disease as well as in suction blisters induced on inflamed, itchy skin (6,39,40). Increased density of several neuropeptides has been shown in the lesional skin of atopic dermati- tis and of psoriasis (41,42). The vascular responses induced by intradermal injection of histamine, SP, NKA and CGRP were shown to be lower com- pared to controls (43). This hyporesponsiveness has been interpreted as being the result of tachyphylaxis.

VIP has been shown to coexist with acetylcho- line in autonomic nerve fibers (44). Acetylcholine induces itch in patients with atopic dermatitis as it induces a burning sensation in controls (45). It may explain why atopic skin itches when sweat- ing. Increased concentrations of VIP have been found in the skin of atopic patients.

Pruritogenic mast cell mediators

Histamine has been known to be a main itch- inducing substance for many years (1). Develop- ment of antihistamines has had an enormous impact not only on the research into itch but also

on its treatment, as they have come to be the most commonly used antipruritic drugs. The fol- lowing is an attempt to find an explanation.

Accumulation of mast cells has been shown in many pruritic, inflammatory skin conditions (46). In the clinical situation, histamine is not released alone but together with other mediators stored or produced after activation of mast cells like chymase and tryptase, platelet-activating factor, leukotrienes, prostaglandin D2, and interleukins 4, 5, 6, and 8.

Histamine induces a flare, weal, and itch that are significantly inhibited by the H1 antagonist, mepyramine, and only partly by the H2 receptor inhibitor, cimetidine (47). This experiment explains why H1 antagonists are widely used in the treatment of itch. Today H3 and H4 receptors are also known (48). The H3 receptors are mainly expressed in the neurons of the peripheral and central nervous system, whereas H1, H2, and H4 receptors are found on mast cells (48). The itch and flare reactions induced by histamine are also reduced by pretreatment with a local anesthetic, lidocaine, indicating that mast cells and nerve fibers constitute a functioning unit.

Mast cell chymase is released together with histamine upon degranulation of mast cells. Rat mast cell chymase was shown to induce flare, weal, and itch in human skin. This itch response was greatly decreased by local depletion of hista- mine using compound 48/80 (49). Mast cell tryptase is also released along with histamine upon degranulation of mast cells and it seems to be an important mediator of itch by its activation of proteinase-activated receptor 2 present on sen- sory nerve fibers and endothelial cells (50).

Activation of mast cells stimulates synthesis of several metabolites of arachidonic acid. Platelet- activating factor is synthesized in activated mast cells. When injected intracutaneously it induces a dose-dependent flare and itch, which is inhibited by the H1 receptor antagonist, mepyramine (51). Leukotrienes (LT) LTC4, and LTD4 are potent vasodiators but do not induce a wheal-and-flare response (52). The antileukotriene, montelukast, has proved to be effective in treating of pruritus in urticaria (53).

Other pruritogenic mediators of inflammation

Mast cell mediators, especially histamine, seem to be very important in the perception of itch. How- ever, clinically there are many types of itch that fall outside this category, simply by not respond- ing to antihistamines.

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Prostaglandins participate in the generation of itch (54). Prostaglandin D is produced by mast cells, being released in urticaria (55). In the skin, prostaglandin E2 induces a slowly progressing erythema (FIG. 3). Prostaglandin E2 induces weak itch and potentates itch induced by histamine (56). Indomethacin, by blocking synthesis of prostag- landin, inhibits the flare response to SP to approxi- mately 60% and to bradykinin to one third (20). The effect of prostaglandins is also dependent on functioning innervation because local anesthetic, lidocaine suppresses the erythema induced by prostaglandin E2 by approximately 30% (20).

Bradykinin injected intracutaneously induces itch that is weaker than histamine-induced itch (57). The flare response to bradykinin is greatly reduced by pretreatment with the H1 receptor inhibitor (mepyramine) and the local anesthetic (lidocaine) and the prostaglandin synthesis inhib- itor (indomethacin) (20,58). Bradykinin B1 and B2 receptors have been found on sensory nerve fibers (59).

Serotonin injected intradermally induces itch that is less potent than that of histamine and is enhanced by PGE2 (60). Serotonin type 3 (5-HT3) receptor is present both in the peripheral and central nervous system, but the serotonin receptor antagonist, tropisetron, has however, not proved to be effective in experimentally induced itch, nor in renal itch (61).

Interleukins, especially IL-2, are known to pro- duce itch. Immunotherapy with IL-2 in the treat- ment of cancer was noted regularly to cause itching (62). On the other hand, cyclosporine, a potent inhibitor of IL-2 production by lymphocytes, is effective in treating itch in atopic dermatitis and other forms of severe pruritus (63,64).

Regulation of pruritoceptive activity in the skin

The interactions between sensory nerve fibers, their transmitters, and other pruritogenic mediators are illustrated in FIG. 3. This cascade of events is dependent on the innervation territories of the neurons, on the density of mast cells, and on the concentration of inflammatory mediators. This in turn will depend on synthesis, release, and degra- dation of the substances involved. For example, SP and bradykinin are degraded by neutral endo- peptidase and angiotensin converting enzyme (62,65). Tryptase cleaves CGRP, whereas chymase and tryptase are degraded by proteases (50,66). This dynamic system contributes to the regulation of the inflammatory response and to the mainte- nance of tissue integrity.

Itch in skin with only slight or no clinical inflammation

In itchy skin disease with an ongoing inflamma- tion, the inflammatory mediators will be continu- ously produced, fueling the firing of sensory nerve fibers. Sometimes, however, the degree of inflam- mation does not correlate with the severity of itch.

Patients with prurigo nodularis may literally dig their skin when scratching, even if the inflam- mation is not pronounced. The most impressive and pathognomonic finding of prurigo nodularis is the presence of thick nerve fiber bundles and fine, reticularly arranged terminal nerve fibers (67). As early as 1899 Johnston wrote in the

Archives of Dermatology

that the number of hypertrophic nerve fibers in prurigo lesions is increased.

It has also been demonstrated that uremic patients undergoing hemodialysis develop a pro- liferation and sprouting of nerve fibers in the epi- dermis (68). Both prurigo nodularis and uremic pruritus can be successfully treated with capsaicin, supporting the importance of the altered cutaneous innervation (69 –71).

“Grenz sensations”: painful itch or itchy pain

In many clinical states of localized itch, burning, and tingling are intermingled. There is often no clinical inflammation in the skin and the symptoms will be elicited by spontaneous firing of neurons without a noxious or pruritogenic stimulus (FIG. 4). The predominating sensation will decide whether the patient seeks a dermatologist or a neurologist. Many of the following entities have been described by neurologists.

Peripheral neuropathic itch

Some localized itchy disorders have no clinical signs of inflammation. Here the neurons can start firing either spontaneously or as a result of pressure on the nerve, which is the case in entrapment syndromes (FIG. 4).

Notalgia paresthetica

Notalgia paresthetica was first described by Ast- wazaturow in 1934 as focal, burning itch on the medial border of the scapula (72). One explana- tion is that the thoracic nerves at the level of T2 to

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T6 penetrate the spinal muscle at a right angle that predisposes them for injury from mild insults (73). Another explanation that has been suggested is an impingement of the nerve root as confirmed by MRI (74). In addition, Springall et al. have found an increased number of dermal sensory nerve fibers in notalgia paresthetica (75). Notalgia paresthetica can be successfully treated with capsaicin (76).

Meralgia paresthetica

Meralgia paresthetica is burning, tingling, and numbness on the anterolateral thigh. The cause is thought to be the result of entrapment of the lateral femoral cutaneous nerve by a fibrous band (77). Obesity, pregnancy, or backpacking are known to predispose or precipitate it.

Backpacking-induced paresthesias

Meralgia, digitalgia paresthetica and tarsal tunnel syndrome are most common. Paresthesias were reported in 96 of 280 long-distance backpackers. A significant risk factor was the distance of march- ing, more than 2000 miles, and the symptoms resolved after hiking (78).

Marcher’s digitalia paresthetica

Marcher’s digitalia paresthetica was first described by Wartenberg in 1954. Tarsal tunnel syndrome is a lesion of the posterior tibial nerve caused by repetitive dorsiflexion of the ankle. It is common among runners and mountain climbers. It was described in Israeli military recruits after 4 weeks

FIG. 4. Schematic illustration of physiological and neuropathic itch. (A) Normally, noxious stimuli in the periphery activate C fibers and the impulses are transmitted to the spinal cord and to the brain. (B) Sometimes, the neurons can be activated without the involvement of peripheral nerve endings. Inflammation at this level can enhance neuronal excitability, causing repetitive activation of the C-fibers. Here the neurons can start firing spontaneously as may be the case in brachioradial pruritus. Photodamaged nociceptors can start firing spontaneously and the nerve impulses generated in this way can also be amplified by neurogenic mechanisms elicited by nerve compression, which is secondary to the cervical spine disease. Nerve fibers can start firing because of pressure; this is the case in such entrapment syndromes as notalgia paresthetica. (C) A lesion can also be located in the spinal ganglia as in herpes infection and postherpetic neuralgia or in spinal cord as in the burning sensation caused by treatment with thalidomide. Modified from Lancet 1999; 353; 1959 – 64.

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of training, and at 9-month follow-up, most were asymptomatic (79).

Cheiralgia paresthetica

Cheiralgia paresthetica describes itch confined to the radial aspect of the lower arm and is caused by the entrapment of the radial nerve. Two cases secondary to handcuff placement were reported (80). In patients where mechanical causes have been excluded, diabetes mellitus should be con- sidered as a possible cause (81).

Brachioradial pruritus

Brachioradial pruritus, a localized itching of the skin on the dorsolateral aspect of the arms, was first described by Waisman in Florida in 1968 as “solar pruritus of the elbows” (82). The present author has found that brachioradial pruritus may be localized not only on the arms but also on the shoulders or neck (83). Another report, from South Africa, by Heyl in 1983, concerned 14 patients with brachioradial pruritus (84). Five of these patients had a history of neck trauma or arthritis. The author suggested that some or even most cases of brachioradial pruritus might be the result of nerve injury in the cervical spine or of nerve compres- sion by other structures. This explanation was supported by Fisher who found that 4 of his 23 patients with brachioradial pruritus suffered from degenerative cervical spine disease (85). Goodkin, Wingard, and Bernhard, in addition to reporting on 22 patients of their own, reviewed the literature on brachioradial pruritus (86). They found that 30 of 98 patients suffered from cervical spine disease.

On the other hand, two reports from Hawaii of a total of 110 patients, supporting the photoneuro- logic theory, the term being coined by Walcyk and Elpern (87,88). In their study concerning 42 patients with brachioradial pruritus, Walcyk and Elpern found 13% to have a history of cervical arthritis,

19% a history of neck trauma, and 10% to be seeing a chiropractor (87). Fifteen of the patients were screened radiologically. All who were over 50 years of age showed pathological cervical radio- graphic findings, whereas 60% of those under 50 years of age showed no abnormalities (87). In a study on 68 brachioradial pruritus patients, Knight and Hayashi found neck pain to be present in six of them only (85). In many patients living in temperate climates, pruritus appears during the summer, remits in the winter, and relapses the following summer (83,89). Brachioradial pruritus can be successfully treated with capsaicin (83,90).

The present author has shown that brachioradial pruritus is associated with a reduction in epidermal nerve fibers and enlargement of nerve fibers in the papillary dermis (91). These findings strikingly resemble the ones the present author observed in the skin after serial phototherapy (FIG. 5A,B) (92). In brachioradial pruritus, the cutaneous innervation of itchy skin normalizes during the symptom-free period. The results indicate that brachioradial pruritus can be elicited by exposure to sunlight or by heat.

The question is if prolonged exposure to sun- light is enough to elicit brachioradial pruritus or if spinal pathology alone can explain the symptoms. Bernhard suggested that both cervical spine disease and sunlight-induced damage to cutaneous nerve endings are important underlying contributors and trigger factors, one setting stage for the other (93).

Double-crush syndrome?

This suggestion might point towards a double-crush syndrome (94). This theory has been postulated by Upton and McComas 1979. They studied 115 patients with carpal tunnel syndrome or cubital tunnel syndrome. Eighty-one of these patients exhibited clinical symptoms of a neural lesion of the neck. According to their hypothesis, the distal part of an axon is easily damaged when another part of that axon is under compression. This theory might explain several of the mononeuropathies described previously.

Spinal neuropathic itch

A lesion can also be located in the spinal ganglia like in herpes infection and postherpetic neuralgia (FIG. 4C) (95). Here the neurons become activated without the involvement of peripheral nerve end- ings. Inflammation at this level can enhance neu- ronal excitability, causing repetitive activation of the C fibers (FIG. 4). Chronic postherpetic neuralgia

FIG. 5. Sensory nerve fibers in the gluteal skin, showing PGP 9.5 immunoreactivity (pan-neuronal marker). (A) Before UV therapy and (B) after 18 treatments with TL01.

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can be successfully treated with capsaicin (96). There can also be a lesion located in the spinal cord, as in the case with the burning sensation induced by treatment with thalidomide (97). Here the neurons can start firing spontaneously as a result of injury induced by the drug.

Cerebral neuropathic itch

Itch can also be induced by a cerebral lesion. Uni- lateral pruritus has been described in 11 patients with cerebral damage caused by stroke or infection in the distribution of the middle cerebral artery, capsula interna, or thalamus on the contralateral side (98 –100). One patient with unilateral pruritus caused by a stroke in the parietal lobe has also been described (101). In these cases pruritus is induced by a spontaneous firing of damaged neurons.

Generalized itch caused by altered concentrations of transmitters of mood

Not only organic lesions in the brain can cause itch but also several psychiatric disorders (102). Itch also influences mood, some patients get agitated, others become depressed (103). Neurotransmitters of depression like dopamine and serotonin are associated with pruritic conditions (60,104). In addition, serotonin is associated with compulsive behaviors like scratching (105). Treatment of Parkinson disease using dopaminergic drugs is related to hallucinations, tactile delusions included (104). Opioid pathways are associated with anxiety and with nociception (106). Opiate-mediated pru- ritus is often severe and may be induced either by endogenous opiates (secondary to liver disease) or morphine administration. It was first described by Bernstein et al., who described relief of intrac- table pruritus with naltrexone, interpreting the effect as a central mechanism on opioid receptors in the CNS (107). The opioid system is also involved in uremic pruritus, which also can be suppressed by naltrexone (108,109).

Conclusion

A distinct pathway of “pure” itch has been deter- mined. In the skin, histamine seems to be the main mediator of itch as depletion of histamine reduces experimental itch induced by several other mediators. In this light it is surprising that antihistamines are not more effective in treatment of clinical itch. Description of burning and tingling itch, a grenz sensation, suggests neuropathic

origin. Localized itch, associated with trauma to peripheral nerves, resolves often after some time of resting.

Acknowledgments

The present paper was supported by grants from Vardal Foundation, Skane County Foundation, and Welander & Finsen Foundation.

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