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Pathophysiology of Pruritus
Pruritus
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Pathophysiology of Pruritus
Kevin]. Shanley, DVM*
Pruritus is a topic that has caused a great deal of controversy because it is difficult to characterize and define. Various indirect definitions proposed include "a sensation which provokes the desire to scratch" 12· 22• 31 · 40 or "an uneasy sensation of irritation in the skin. "22 Pruritus is synonymous with itch and is derived from the Latin word "prurire," which means "to itch." Pruritus is often misspelled "pruritis," which incorrectly classifies it as inflammation. 25 More correctly, it is a symptom or sign of inflammatory skin disease. Throughout history, men have penned diametrically opposed interpretations of itch and scratching. Positive views include the proverbs "tis better than riches to scratch where it itches" and "scratching is one of natures sweetest pleasures, and nearest at hand. " 25 Back scratchers have been in vogue as early as Elizabethan times. In the 18th century, it was customary for a young man to present his future wife with a back scratcher. 2 Scotsmen use the humorous phrase "God bless the Duke of Argyle" when they scratch themselves. Legend has it that the Duke of Argyle erected posts for his cattle to rub against. His herdsmen would use this phrase when they rubbed their backs against these posts. The negative viewpoint on itching includes, "The itch is a mean, unconfessable ridiculous malady; one can pity someone who is suffering; someone who wants to scratch himself makes one laugh. " 25 Socrates frequently reported the mixed sensations of pain and pleasure associated with itching and scratching. Napoleon's characteristic stance with his left hand behind his back has been proposed by some as a mask for scratching. Scabies and dermatitis herpetiformis have been suggested as causes of his pruritic skin condition. 18 Other definitions of pruritus include the following: 1. Epicritic itch-A spontaneous, sharp, well-demarcated pruritus. 31 2. Protopathic itch-Pruritus that is poorly localized and possesses a burning quality. 31 *Diplomate, American College of Veterinary Dermatology; Assistant Professor, Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania Veterinary Clinics of North America: Small Animal Practice- Vol. 18, No. 5, September 1988
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3. Spontaneous itch-Well-localized itch at the site of itch stimulation that persists briefly after the stimulus is removed. 6 4. Itchy skin-A poorly localized area adjacent to the site of itch stimulation that doesn't itch spontaneously, but is hyperresponsive when exposed to a minor stimulus such as light touch. 5. Physiologic itch-A short-lived response in skin to the common environmental stimuli that may or may not provoke scratching. 40 6. Pathologic itch-An intense skin response occurring with pathologic changes that provokes severe scratching. 40 7. Scattered itch-Multiple distant areas of pruritus present in the skin following previous stimulation of itch at one primary site. 40 8. Referred itch-Development of a focal area of pruritus during scratching of a primary pruritic site. This is similar to scattered itch. 13 9. Conversion itch-The change of a normal cutaneous sensory experience (that is, touch) into pruritus. 40 Research in the field of pruritus has been slow, arduous, and confusing. A great deal of what is known about pruritus has been extrapolated from pain research. 19· 35 There are aspects of pruritus that overlap pain and touch sensations. It is generally accepted that pain and pruritus are transmitted on the same afferent nerve fibers, 22 although they are perceived as separate entities. Pain may occur in many organs, whereas pruritus is limited to the skin. Current research proposes the following sequence of events for pruritus: stimulus~ mediato~ recepto~ peripheral pathway~ central processing~ central interpretation~ response. 25 A specific end-organ for pruritus has not been found. It is still unknown if there is a common chemical mediator for itch. There is an absolute paucity of information in the veterinary literature regarding the pathophysiology of pruritus in the dog and cat.
NEUROANATOMY To understand the pathogenesis of pruritus, it is necessary to have an understanding of neuroanatomy and neurophysiology. Prior to the 1800s, skin was perceived as only capable of representing touch, the fifth sense. In addition to providing the primary sense of touch, skin further defines the sensory modalities of pain, pressure, heat, cold, and pruritus. The general somatic afferent portion of the nervous system is referred to as the "pain, temperature (heat and cold), touch" system. 11 Somatosensory receptor units are functionally classified as thermoreceptors (heat and cold), mechanoreceptors (touch, pressure), and nociceptors (pain, itch). Nociceptors are polymodal, in that they respond to thermal, chemical, and mechanical stimuli. 31 The majority of mechanoreceptors are supplied by A alpha fibers, whereas thermoreceptors and nociceptors are supplied by A delta and C fibers. A delta fibers are myelinated and conduct nervous stimuli at approximately 15 meters pe r second. They carry sensations of pain, tactile temperature, and epicritic itch (spontaneous, well-localized itch). The C fibers are nonmyelinated, slow-conducting (approximately 2 meters per second) fibers with a high threshold for stimulation. They carry
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sensations of dull, burning pain and protopathic itch (poorly localized, burning itch). Both types of fibers enter the dorsal root of the spinal cord via the substantia gelatinosa, where they synapse on cell bodies at the base of the dorsal grey column. These axons then cross over to the opposite lateral spinothalamic tract. In primates, this crossover is essentially complete, 22 whereas in domestic animals, there is a near equal distribution of fibers bilaterally, or a slight dominance of the contralateral pathway.U· 31 The axons proceed cranially through the spinal cord, medulla, pons, and midbrain to synapse in the caudal thalamus. These final (tertiary or third order) axons ascend to the sensory cortex by way of the internal capsule.U· 31 Conscious pain perception can occur at either the thalamus or the cortex. Once stimuli reach the sensory cortex, they may be modified by other cutaneous experiences or competing emotional or other central modifYing factors. Itch sensations can be ignored, adapted to, or develop into pathologic itch depending on the state of the central nervous system and the effects of modulating factors. 40 PRURITUS VERSUS PAIN
Pruritus and pain are easy sensations to separate clinically, but have many similarities in their pathways and various other properties. Proponents of early theories on pruritus believed that itch was a submodality of pain and considered it subthreshold pain. However, itch is best understood as a primary sensory modality. In people, a variety of diseases and conditions affecting pain, itch, and touch have shown the following confusing results. Heating skin to 41oc will eliminate the ability to perceive itch, but will cause pain. 3 1 If heat is applied long enough at inadequate levels to cause pain, it will cause itch. 24 Oral ingestion of opiates will diminish pain but intensifY itch. 31 Patients with a congenital inability to feel cutaneous pain are also unable to perceive itch sensations. Tabes dorsalis, a degenerative disease of the spinal cord and sensory nerve trunks, is characterized by paroxysms of intense pain and loss of touch with maintenance of the ability to perceive pruritus. 31 In leprosy, lesions that are insensitive to pain are also unable to elicit itch. Skin that has been denuded of its epidermis and superficial dermis will show pain but is unable to elicit pruritus. 3 1 Patients with lateral spinothalamic tract hemiocordotomy retain touch sensations, but lose the ability to perceive pain or pruritus. 6 With pain, the normal reflex is to withdraw from or avoid the painful stimulus, whereas the normal reflex with pruritus is to rub or scratch. Histamine injected intradermally will elicit pruritus in 10 to 50 seconds, whereas deep injections will cause pain. Methylbromide applied to the skin topically in low concentrations first causes itching, which is followed by burning pain, then deep, aching pain. 25 Light pressure with a fine probe will elicit pruritus, whereas increased pressure causes pain. 25 Therefore, itch currently is considered a primary cutaneous sensation, and not a subthreshold of pain. With lumbar anesthesia, progressing hypalgesia will inhibit cowhage (a legume) spicules from causing itch even though a pinprick will still cause pain. 33 As anesthesia progresses, a pinprick will cause itch and finally no pruritus is perceived,
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even though touch and temperature sensations remain. Cowhage and electrical stimulation used to provoke pruritus will cause increased itching proportional to the frequency of stimulation. The sensation will not change to pain. Similarly, as low-grade pain resolves, it does not change character to pruritus.
THEORIES ON CUTANEOUS SENSATION The earliest theories on cutaneous sensations and pruritus proposed separate, specific end organs, afferent nerve supplies, and central foci for perception of each of the cutaneous sensations. These "specificity theories" were very simplistic and suggested that histologically distinct end organs accounted for each sensation. Pain was associated with free epidermal nerve endings, pressure with free nerve endings adjacent to hair follicles or Meissner corpuscles in the palms and soles, warmth with deep Ruffini endings, and cold with superficial Krause bulbs. Pruritus did not fit into this category because it was not considered a primary sensory modality. Additional research was geared toward pain perception, and itch was either ignored or considered a submodality of pain. Not untill950 did experiments distinguish pruritus with a "pricking quality" from that with a "burning quality. " 19 These experiments separated pruritus from touch, but still suggested that the two types of pruritus (epicritic and protopathic) corresponded to the two types of pain (epicritic and protopathic) and that epicritic (sharp, well-defined) pruritus and pain followed myelinated nerve fibers, whereas protopathic (diffuse, slow) pruritus and pain followed unmyelinated nerve fibers. A second major theory on cutaneous sensation is the pattern theory. This theory is diametrically opposed to the specificity theory. It states that cutaneous stimulation of nonspecific receptors is carried on nonspecific afferent nerve fibers to the brain. The brain recognizes the pattern of nerve impulses as a learned sensation, such as touch, pruritus, or pain. This theory is based on studies that showed no qualitative differences found in a variety of afferent nerve fibers when different cutaneous stimuli were applied. Therefore, it was surmised that the brain must be capable of distinguishing specific cutaneous sensations based on the characteristic pattern of stimulation it received. 36 This pattern was defined as the temporal and spatial relations of the nervous impulses. Probably there are portions of both theories that are correct. Gate Control Theory The gate control theory of pain was proposed in 1965. 32 It stated that the cells of the substantia gelatinosa of the dorsal horn of the spinal cord act as a swinging gate to dampen or accentuate afferent nerve patterns from large and small nerve fibers before they stimulate central transmission cells in the dorsal horn. These central transmission cells then activate nerve fibers to cause stimulation of an action system that is responsible for pain perception and response of the individual. It also states that the pattern of nerve impulses influences various parts of the brain to modulate the gate
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control system. Although this theory is quite complex, suffice it to say that the substantia gelatinosa cells modify afferent impulses from peripheral fibers to central cells. Central factors such as anxiety, previous experiences, boredom, or competing cutaneous sensations may act as a check and balance system on the substantia gelatinosa cells to either reduce or amplify the sensations of pain or pruritus. 12• 14• 31 This helps explain why pruritus often is perceived as being more intense at night, because other sensory input is low. The gate control theory was proposed to explain pain sensation, but the general concept of gating also has been accepted to explain pruritus. MEDIATORS It is not known whether a final common mediator of all pnuitus exists. Histamine has been suggested as a final mediator, but intradermal reactions take 10 to 50 seconds to cause pruritus, which does not support this idea. 25• 31 This latency may be due to slow accumulations of cyclic AMP. 25
Histamine Histamine is the first recognized pruritogen25 and is thought of as the classic mediator of pruritus. 31 Histamine is produced by mast cells in the dermis and stored in cytoplasmic granules in the mast cells. 22 As was mentioned earlier, intradermal injections of histamine cause pruritus, particularly if injected at the level of the dermoepidermal junction. 25 A deep injection of histamine will cause pain, especially if given in relatively large doses. 12 Intravenous injections of histamine will cause flushing, headaches, and edema but not pruritus. Single intradermal injections of histamine cause wheal formation and axonal flare in addition to pruritus. Following intradermal injections of histamine, it has been shown that vasodilatation (with its accompanying erythema) and increased vascular permeability (with the clinically perceived wheal) are influep.ced by H 1 and H2 receptors. 30 Itch and axon flare, however, only involve receptors of the H 1 type. Histamine acts on leukocyte H 2 receptors to inhibit additional histamine release. H 2 blockers reduce this negative-feedback effect. Also, H2 blockers inhibit the histamine degrading enzyme N-methyltransferase and therefore may actually exacerbate pruritus. 21 This helps explain why H 2 blockers (such as cimetidine and ranitidine) are of no value in the treatment of pruritus, and why H 1 blockers (the "classic" antihistamines) are only partially effective . In man, an age-related change occurs in that less pruritus is perceived in people more than 50 years old, even though the objective changes (wheal and flare) remain constant. 9 This has not been reported to occur in dogs and cats. It has been suggested that central sedation is more important than H 1 receptor antagonism for antipruritic effects in nonurticar'ial dermatoses. 27 However, in diseases in which wheal formation occurs due to histamine release, the H 1 blockers are effective. Because most patients with chronic pruritus respond poorly to antihistamines and do not show classic histamineinduced changes (wheal and flare), histamine probably is not the primary mediator of pruritus in these patients. 38
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Proteases, Peptides, and Cowhage Some of the earliest research on pruritus involved the use of cowhage as a pruritogen. 19· 25· 31· 33• 35 Cowhage is a legume, Mucuna pruriens, which has barbed spicules that act as a protective cover for the bean pods. 25 Cowhage was first described in English in 1688, although its pruritic properties were well known much earlier by natives. Cowhage grows in the tropics, including South America, Africa, India, and Central America. The name "cowhage" is thought to be a poor translation of the Hindu word "kiwach," which means "bad rubbing. "25 In the late 1700s, it was noted that boiling the spicules eliminated their pruritogenic properties. It was not until 1955, however, that Shelly and Arthur showed that the pruritus was due to the endopeptidase mucunain, and not to the mechanical trauma from the barbed spicules. 34 If the spicule was placed superficially, itching could be elicited without the development of erythema or wheals. Intradermal insertion of cowhage spicules produced pruritus in 15 to 30 seconds. Co~hage can cause pruritus in skin depleted of its histamine. These findings suggest that mucunain is not the final mediator of pruritus and that histamine was not involved with the pruritus from spicules. Other proteases have also been suggested as pruritic agents, which is an attractive hypothesis in light of all of the proteases released from the skin and blood during the acute phase of inflammation. Suggested endogenous proteases include trypsin, chymotrypsin, and fibrinolysin . Exogenous proteases such as ficin, papain, and streptokinase also induce itch. Some proteases can be boiled to destroy their proteolytic activity; however, their pruritogenic properties remain unchanged. Proteases are potent histamine liberators, and it is likely their pruritic properties are due to this effect, rather than mechanisms independent of histamine. 15 Substance P Substance P is an undecapeptide neurotransmitter that has been identified in the afferent neurons of cat and rat skin, where it produces vasodilatation and increased vascular permeability. 26 Substance P is also found in the brain and spinal cord and in the nerve supply to the gastrointestinal tract. 29 Two distinct subclasses of substance P receptors have been proposed. 39 Substance P is a pote nt histamine liberator, and its effects are inhibited by H 1 antihistamines, suggesting that most or all of its effects are indirect. Serotonin, bradykinin, and lysylbradykinin may also play a role in the genesis of pruritus. 31 • 38 Opiate Peptides Opioid peptides such as leucine enkephalin (leu-enkephalin) and methionine enkephalin (met-enkephalin) are found throughout the central and peripheral nervous systems. Systemic administration of morphine relieves pain but causes pruritus by acting centrally on opioid receptors. Morphine will potentiate the pruritus evoked by histamine . 16 · Naloxone hydrochloride (Narcan) is a selective opiate antagonist that has been shown to inhibit the central perception of pruritus experimentally induced by histamine. 5 Peripheral effects of naloxone on pruritus are more contradictory, in that naloxone failed to reduce the duration of the itch
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response. 16 Currently, most evidence implies that opioid peptides in the central nervous system act as mediators in the perception of pruritus. Opiate antagonists may play a much greater role in the control of pruritus in the future. Prostaglandins In normal, uninflamed skin, prostaglandins are present in insignificant amounts. In the presence of excess arachidonic acid (substrate), prostaglandins are rapidly synthesized in the skin. 20 This suggests that the presence of prostaglandins in inflammatory skin diseases is due to local biosynthesis rather than release from existing stores. Increases in arachidonic acid .concentrations during inflammation probably provide the stimulus for this biosynthesis. In arachidonic acid metabolism, a variety of pro-inflammatory agents are produced. The lipoxygenase pathway results in the formation of leukotrienes, whereas prostaglqndins are produced in the cyclooxygenase pathway of arachidonic acid metabolism . . Prostaglandin E 1 (PGE 1) is unable to cause pruritus by itself, 22 but it significantly lowers the itch threshold in human skin in vivo to pruritus that has been experimentally induced by histamine and papain. 28 Prostaglandin E 2 and PGH 2 (an unstable prostaglandin endoperoxide that is formed as an intermediate metabolite in the arachidonic acid pathway) are capable of producing pruritus, although PGE 2 is more potent. When given with histamine, both PGE 2 and PGH 2 produced a greater degree of pruritus and flare than can be explained by their cumulative effects. This suggests that prostaglandins and their intermediates may potentiate the pruritus and flare reaction in inflammatory skin diseases. 8 • 23 Prostaglandin E 2 and PG F 2 alpha biosynthesis in skin is inhibited by flucinolone and hydrocortisone, although the inhibition of PGE 2 by hydrocortisone is not statistically significant. 20 This indicates that at least some of the anti-inflammatory properties of corticosteroids are due to antiprostaglandin effects. Leukotrienes Most experimental work with leukotrienes is aimed at defining local inflammatory changes with little information available regarding their role in pruritus or pain. 8 • 37 Leukotriene (LT) C4, 0 4 , and E 4 are components of slow-reacting substance of anaphylaxis (SRS-A) and cause formation of erythema and wheals when injected intradermally. 37 Dermal capillaries and superficial and deep venules showed dilatation and endothelial cell activation, whereas arterioles only became dilated. This erythema and whealing are dose-related. Leukotriene 0 4 and LTE 4 may cause transient burning on injection but not pruritus. Leukotriene B4 (LTB4 ) is one of the most potent neutrophil chemoattractants known. In one of four subjects, intradermal injection of LTB4 caused persistent pruritus. 8 Prostaglandin 0 2 is the primary product in human mast cell arachidonic acid metabolism. By itself, PGD 2 causes intradermal wheal and erythema formation with little neutrophil accumulation. When injected intradermally together, PGD2 and LTB4 cause tenderness and a much greater degree of edema and accumulation than can be explained by their cumulative effects. This suggests that PGD 2 and LTB4 act in synergy37 as mediators of inflammation. Currently,
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however, there is no evidence that leukotrienes are directly involved with pruritus. 12
PERCEPTION OF PRURITUS Once pruritus has been initiated, there are numerous central factors and adjunct influences on the perception of pruritus. Dry skin (xerosis) is frequently seen in environments with low ambient humidity, and will lower the pruritic threshold. In man, various anatomic locations, such as the wrist and face, have a low threshold for itching. 22 Age also affects pruritus. Intradermal injections of histamine will produce consistent erythema and wheal formation, but the degree of pruritus perceived will lessen as people age.9 Whether this phenomenon occurs in dogs and cats is unknown. A pinprick near a pruritic focus or in the same dermatome will at least temporarily abolish the itch. 4 • 25 Likewise, cold, heat, ultraviolet radiation, and vibration will also diminish . pruritus. Experimentally induced itch is abolished in human patients with atopic dermatitis by cooling the skin surface. 17 Heating the skin surface will aggravate this same itch in one third of the patients and abolish or diminish the pruritus in two thirds of these patients. According to the gate control theory, these competing cutaneous sensations may act to reduce the cognizant perception of the itch spot via spinal modulation of afferent stimuli. Anxiety, excitement, and heightened states of alertness may have selective enhancement or suppression of the perception of pruritus. 25 · Acupuncture has also been shown to influence pruritus. Patients with experimental histamine-induced itch and flare were treated with acupuncture, were treated with application of acupuncture needles near acupuncture points (pseudoacupuncture), or were not given any treatment, 15 minutes prior to histamine injection. 3 Acupuncture had little effect on the onset time of pruritus or on the maximum itch intensity. However, acupuncture had a statistically significant dampening effect on the size of maximal flare, on the duration of itch, and on the overall (cumulative) itch perceived. Pseudoacupuncture had only minimal effect, suggesting that the acupuncture points are rather specific. However, it must be noted that the induced pruritus was mild and that severe pruritus may not respond in a similar manner.
SCRATCHING The exact relationship between itch and scratch is unknown. Why does scratching relieve itching? Scratching in response to itch is a spinal reflex, although it is modified by input from higher centers, including the frontal cortex. 7 It has been proposed that scratching substitutes pain for itch. This is unlikely, because the slight pain from several pinpricks will abolish itch in adjacent areas of skin for up to 45 seconds, even though the pain disappears within 15 seconds. Another explanation suggests that scrat~hing
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damages sensory nerve endings and that the delay in the return of pruritus may be the time required for regeneration of these endings. 22 Scratching patterns show that the length of the scratch stroke decreases as the pruritus progresses distally on the extremities-that is, scratch strokes are shortest on the fingers and toes, and longest on the proximal extremities and trunk. 10 It was suggested that this was due to the concentration of tactile receptors, because tactile receptors are more concentrated on the fingers and toes, and less concentrated on the proximal extremities and trunk. Scratch strokes need to be longer on the trunk in order to adequately stimulate tactile receptors, but they are short on the fingers, where tactile receptors are close together. 10 Referred itch is an odd phenomenon present in approximately 20 per cent of people. 13 It is a sensation of pruritus that occurs somewhere else on the body when a primary itch is scratched. When an itch sensation occurs, this referred itch is ipsilateral to the primary itch, well-localized, shortlived, and reproducible. 13 Scratching the legs and trunk most frequently produced referred itch, whereas the face, palms, and soles rarely produced referred itch. The referred itch usually occurs at a higher segmental level in the nervous system, when compared to the primary itch site. If symmetr;ical sites on each side of the body are stimulated to itch, the referred itch sites are not symmetrical. Stimulating identical sites on different individuals does not result in identical sites of referred itch, indicating that this is an individual response. This is an interesting concept to consider as a plausible explanation of severe generalized pruritus in an allergic dog. Paroxysmal pruritus is a controversial topic in human dermatology that explains a type of severe pruritus that results in self-mutilation. Arnold suggests that this itching originates in the central nervous system as a result of a strong emotional state (that is, anger, guilt, resentment). 1 This misplaced release of energy results in bursts or paroxysms of severe itching. There is a concomitant extraordinary elevation in the pain threshold to this site of pruritus. Rather than feeling intense pain, these patients report feelings of tremendously gratifYing pleasure. Once pain is finally felt, the itching immediately ceases and does not return until the damaged skin heals. This severe pruritus has not been reported in the veterinary literature; however, it may partially explain why some dogs and cats scratch or chew their skin to cause severe damage. The author is aware of a male Great Dane with probable cauda equina syndrome that self-amputated the distal half of its tail by chewing through it at the midpoint. One can only speculate that there were both a severe pruritus and a tre mendous increase in pain tolerance .
SUMMARY In spite of the research that has been performed , pruritus remains a poorly understood sensation. It is important to remember that the majority of information presented here is derived from observations of human
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subjects. One can only speculate as to how much of this information can be extrapolated to pruritus in animals. Pruritus is closely intertwined with pain and touch. Pain and pruritus sensations are carried on A delta and C fibers, ascend on the lateral spinothalamic tract, and terminate in various brain centers, including the thalamus and the cortex. The gate control theory of pain and pruritus describes the substantia gelatinosa cells as "swinging gates" to modify peripheral input and result in stimulation of higher centers. Central factors reduce or amplify the perception of these cutaneous sensations. Histamine is the classic mediator of pruritus, although it is still unknown whether a final common mediator of pruritus exists. Numerous other medtators include proteases, peptides, substance P, opiate peptides, prostaglandins, and leukotrienes. These may have pruritic properties directly, or may act as histamine liberators to cause pruritus.
REFERENCES 1. Arnold HL: Paroxysmal pruritus: Its clinical characterization and a hypothesis of its pathogenesis. J Am Acad Dermatol 11:322, 1984 2. Ayres S: The fine art of scratching. JAm Med Assoc 189:1003, 1964 3. Bellgrade MJ, Solomon LM, Lichter EA: Effect of acupuncture on experimentally induced itch. Acta Derm Venereol (Stockh) 64:129, 1984 4. Bernhard JD: In Fitzpatrick TB, Eisen AZ, Wolf K, et al (eds): Dermatology in General Medicine. Edition 3. New York, McGraw-Hill, 1987 5. Bernstein JE, Swift RM, Soltain K, et al: Antipruritic effect of an opiate antagonist, naloxone hydrochloride. J Invest Dermatol 78:82, 1982 6. Bickford RG: Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin Sci 3:377, 1938 7. Bradford FK: Ablations of frontal cortex in cats with special reference to enhancement of the scratch reflex. J Neurophysiol 2:192, 1939 8. Camp RDR, Coutts AA, Greaves MW, et al: Responses of human skin to intradermal injection of leukotrienes C,, D, , and B,. Br J Pharmacol 80:497, 1983 9. Cormia FE: Experimental histamine pruritus. J Invest Dermatol 19:21, 1952 10. Cornblett T: Scratching patterns. J Invest Dermatol 20:105, 1953 11. de Lahunta A: Veterinary Ne uroanatomy and Clinical Neurology. Edition 2. Philadelphia, WB Saunders Co, 1983 12. Denman ST: A review of pruritus. J Am Acad Dermatol 14:375, 1986 13. Evans PR: Referred itch (mitempfindungen). Br Med J 2:839, 1976 14. Fjellen B, Hagermark 0: Transcutaneous nerve stimulation and itching. Acta Dermatol 58:131, 1978 15. Fjellen B, Hagermark 0: Studies on pruritogenic and histamine-releasing effects of some putative peptide neurotransmitters. Acta Dermatol 61:245, 1981 16. Fjellen B, Hagermark 0: The influence of the opiate antagonist naloxone on experimental pruritus. Acta Derm Venereol (Stockh) 64:73, 1984 17. Fruhostorfer H, Hermanns M, Latzke L: The effects of thermal stimulation on clinical and experimental itch. Pain 24:259, 1986 18. Friedman R: Emperor's itch: Legend concerning Napoleon's affiiction with scabies. Bull Hist Med 8:949, 1940 19. Graham DT, Goodell H, Wolff H : Neural mechanisms involved in itch, "itchy skin" and tickle sensations. J Clin Invest 30:37, 1951 20. Greaves MW, McDonald-Gibson W: Inhibition of prostaglandin biosynthesis by corticosteroids. Br Med J 2:83, 1972 21. Greaves MW: H2 receptor antagonists and delayed hypersensitivity. Lancet 1:880, 1978 22. Greaves MW: In Fitzpatrick TB, Eisen AZ, Wolf K, et al (eds): Dermatology in General Medicine. Edition 3. New York, McGraw-Hill, 1987
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23. Hagermark 0: Potentiation of itch and Hare responses in human skin by PGE2 and PGH 2 and a prostaglandin endoperoxide analog. J Invest Dermatol 69:527, 1977 24. Hardy JD, Wolf HG, Goodell H: Experimental evidence on the nature of cutaneous hyperalgesia. J Clin Invest 29:115, 1950 25. Herndon JH: Itching: The pathophysiology of pruritus. lnt J Dermatol 14:465, 1975 26. Jorizzo JL, Coutts AA, Eady RAJ, et al: Vascular responses of human skin to injection of substance P and mechanism of action. Eur J Pharmacol 87:67, 1983 27. Krause L, Shuster S: Mechanism of action of antipruritic drugs. Br Med J 287:119, 1983 28. Lovell CR, Burton PA, Duncan EHL, et al: Prostaglandins and pruritus. Br J Dermatol ...g4:273, 1976 29. Luttgen PJ: An outline of neurotransmitters and neurotransmission. Part II. Function and dysfunction. J Am Anim Hosp Assoc 23:663, 1987 30. Marks R, Greaves MW: Vascular reactions to histamine and compound 48/80 in human skin: Suppression by a histamine H2 blocking agent. Br J Clin Pharmacol 4:367, 1977 31. Martin J: Pruritus. lnt J Dermatol 24:634, 1985 32. Melzack R, Wall PO: Pain mechanisms: A new theory. Science 150:971, 1965 33. Rothman S: In Montagna W (ed): Advances in Biology of the Skin. Volume I. Oxford, Pergamon Press, 1960 34. Shelly WB, Arthur RP: Studies on cowhage (Mucuna pruriens) and its pruritogenic proteinase, mucunain. Arch Dermatol 72:399, 1955 35. Shelly WB, Arthur RP: The neurohistology and neurophysiology of the itch sensation in man. Arch Dermatol 76:296, 1957 36. Sinclair DC: Cutaneous sensation and the doctrine of specific energy. Brain 78:584, 1955 37. Soter NA, Lewis RA, Corey EJ, et al: Local effects of synthetic leukotrienes (LTC,, LTD,, LTE 4, and LTB,) in human skin. J Invest Dermatol 80:115, 1983 38. Tuckett RP, Denman ST, Chapman CR, et al: Pruritus, cutaneous pain, and eccrine gland and sweating disorders. JAm Acad Dermatol11:1000, 1984 39. Watson SP, Sandberg BEB, Hanley MR, et al: Tissue selectivity of substance P alkyl esters: Suggesting multiple receptors. Eur J Pharmacol87:77, 1983 40. Winkelmann RK: Pharmacologic control of pruritus. Med Clin North Am 66:1119, 1982 Department of Clinical Studies School of Veterinary Medicine University of Pennsylvania 3850 Spruce Street Philadelphia, Pennsylvania 19104
0195-5616/88 $0.00
+ .20
Pathophysiology of Pruritus
Kevin]. Shanley, DVM*
Pruritus is a topic that has caused a great deal of controversy because it is difficult to characterize and define. Various indirect definitions proposed include "a sensation which provokes the desire to scratch" 12· 22• 31 · 40 or "an uneasy sensation of irritation in the skin. "22 Pruritus is synonymous with itch and is derived from the Latin word "prurire," which means "to itch." Pruritus is often misspelled "pruritis," which incorrectly classifies it as inflammation. 25 More correctly, it is a symptom or sign of inflammatory skin disease. Throughout history, men have penned diametrically opposed interpretations of itch and scratching. Positive views include the proverbs "tis better than riches to scratch where it itches" and "scratching is one of natures sweetest pleasures, and nearest at hand. " 25 Back scratchers have been in vogue as early as Elizabethan times. In the 18th century, it was customary for a young man to present his future wife with a back scratcher. 2 Scotsmen use the humorous phrase "God bless the Duke of Argyle" when they scratch themselves. Legend has it that the Duke of Argyle erected posts for his cattle to rub against. His herdsmen would use this phrase when they rubbed their backs against these posts. The negative viewpoint on itching includes, "The itch is a mean, unconfessable ridiculous malady; one can pity someone who is suffering; someone who wants to scratch himself makes one laugh. " 25 Socrates frequently reported the mixed sensations of pain and pleasure associated with itching and scratching. Napoleon's characteristic stance with his left hand behind his back has been proposed by some as a mask for scratching. Scabies and dermatitis herpetiformis have been suggested as causes of his pruritic skin condition. 18 Other definitions of pruritus include the following: 1. Epicritic itch-A spontaneous, sharp, well-demarcated pruritus. 31 2. Protopathic itch-Pruritus that is poorly localized and possesses a burning quality. 31 *Diplomate, American College of Veterinary Dermatology; Assistant Professor, Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania Veterinary Clinics of North America: Small Animal Practice- Vol. 18, No. 5, September 1988
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3. Spontaneous itch-Well-localized itch at the site of itch stimulation that persists briefly after the stimulus is removed. 6 4. Itchy skin-A poorly localized area adjacent to the site of itch stimulation that doesn't itch spontaneously, but is hyperresponsive when exposed to a minor stimulus such as light touch. 5. Physiologic itch-A short-lived response in skin to the common environmental stimuli that may or may not provoke scratching. 40 6. Pathologic itch-An intense skin response occurring with pathologic changes that provokes severe scratching. 40 7. Scattered itch-Multiple distant areas of pruritus present in the skin following previous stimulation of itch at one primary site. 40 8. Referred itch-Development of a focal area of pruritus during scratching of a primary pruritic site. This is similar to scattered itch. 13 9. Conversion itch-The change of a normal cutaneous sensory experience (that is, touch) into pruritus. 40 Research in the field of pruritus has been slow, arduous, and confusing. A great deal of what is known about pruritus has been extrapolated from pain research. 19· 35 There are aspects of pruritus that overlap pain and touch sensations. It is generally accepted that pain and pruritus are transmitted on the same afferent nerve fibers, 22 although they are perceived as separate entities. Pain may occur in many organs, whereas pruritus is limited to the skin. Current research proposes the following sequence of events for pruritus: stimulus~ mediato~ recepto~ peripheral pathway~ central processing~ central interpretation~ response. 25 A specific end-organ for pruritus has not been found. It is still unknown if there is a common chemical mediator for itch. There is an absolute paucity of information in the veterinary literature regarding the pathophysiology of pruritus in the dog and cat.
NEUROANATOMY To understand the pathogenesis of pruritus, it is necessary to have an understanding of neuroanatomy and neurophysiology. Prior to the 1800s, skin was perceived as only capable of representing touch, the fifth sense. In addition to providing the primary sense of touch, skin further defines the sensory modalities of pain, pressure, heat, cold, and pruritus. The general somatic afferent portion of the nervous system is referred to as the "pain, temperature (heat and cold), touch" system. 11 Somatosensory receptor units are functionally classified as thermoreceptors (heat and cold), mechanoreceptors (touch, pressure), and nociceptors (pain, itch). Nociceptors are polymodal, in that they respond to thermal, chemical, and mechanical stimuli. 31 The majority of mechanoreceptors are supplied by A alpha fibers, whereas thermoreceptors and nociceptors are supplied by A delta and C fibers. A delta fibers are myelinated and conduct nervous stimuli at approximately 15 meters pe r second. They carry sensations of pain, tactile temperature, and epicritic itch (spontaneous, well-localized itch). The C fibers are nonmyelinated, slow-conducting (approximately 2 meters per second) fibers with a high threshold for stimulation. They carry
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sensations of dull, burning pain and protopathic itch (poorly localized, burning itch). Both types of fibers enter the dorsal root of the spinal cord via the substantia gelatinosa, where they synapse on cell bodies at the base of the dorsal grey column. These axons then cross over to the opposite lateral spinothalamic tract. In primates, this crossover is essentially complete, 22 whereas in domestic animals, there is a near equal distribution of fibers bilaterally, or a slight dominance of the contralateral pathway.U· 31 The axons proceed cranially through the spinal cord, medulla, pons, and midbrain to synapse in the caudal thalamus. These final (tertiary or third order) axons ascend to the sensory cortex by way of the internal capsule.U· 31 Conscious pain perception can occur at either the thalamus or the cortex. Once stimuli reach the sensory cortex, they may be modified by other cutaneous experiences or competing emotional or other central modifYing factors. Itch sensations can be ignored, adapted to, or develop into pathologic itch depending on the state of the central nervous system and the effects of modulating factors. 40 PRURITUS VERSUS PAIN
Pruritus and pain are easy sensations to separate clinically, but have many similarities in their pathways and various other properties. Proponents of early theories on pruritus believed that itch was a submodality of pain and considered it subthreshold pain. However, itch is best understood as a primary sensory modality. In people, a variety of diseases and conditions affecting pain, itch, and touch have shown the following confusing results. Heating skin to 41oc will eliminate the ability to perceive itch, but will cause pain. 3 1 If heat is applied long enough at inadequate levels to cause pain, it will cause itch. 24 Oral ingestion of opiates will diminish pain but intensifY itch. 31 Patients with a congenital inability to feel cutaneous pain are also unable to perceive itch sensations. Tabes dorsalis, a degenerative disease of the spinal cord and sensory nerve trunks, is characterized by paroxysms of intense pain and loss of touch with maintenance of the ability to perceive pruritus. 31 In leprosy, lesions that are insensitive to pain are also unable to elicit itch. Skin that has been denuded of its epidermis and superficial dermis will show pain but is unable to elicit pruritus. 3 1 Patients with lateral spinothalamic tract hemiocordotomy retain touch sensations, but lose the ability to perceive pain or pruritus. 6 With pain, the normal reflex is to withdraw from or avoid the painful stimulus, whereas the normal reflex with pruritus is to rub or scratch. Histamine injected intradermally will elicit pruritus in 10 to 50 seconds, whereas deep injections will cause pain. Methylbromide applied to the skin topically in low concentrations first causes itching, which is followed by burning pain, then deep, aching pain. 25 Light pressure with a fine probe will elicit pruritus, whereas increased pressure causes pain. 25 Therefore, itch currently is considered a primary cutaneous sensation, and not a subthreshold of pain. With lumbar anesthesia, progressing hypalgesia will inhibit cowhage (a legume) spicules from causing itch even though a pinprick will still cause pain. 33 As anesthesia progresses, a pinprick will cause itch and finally no pruritus is perceived,
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even though touch and temperature sensations remain. Cowhage and electrical stimulation used to provoke pruritus will cause increased itching proportional to the frequency of stimulation. The sensation will not change to pain. Similarly, as low-grade pain resolves, it does not change character to pruritus.
THEORIES ON CUTANEOUS SENSATION The earliest theories on cutaneous sensations and pruritus proposed separate, specific end organs, afferent nerve supplies, and central foci for perception of each of the cutaneous sensations. These "specificity theories" were very simplistic and suggested that histologically distinct end organs accounted for each sensation. Pain was associated with free epidermal nerve endings, pressure with free nerve endings adjacent to hair follicles or Meissner corpuscles in the palms and soles, warmth with deep Ruffini endings, and cold with superficial Krause bulbs. Pruritus did not fit into this category because it was not considered a primary sensory modality. Additional research was geared toward pain perception, and itch was either ignored or considered a submodality of pain. Not untill950 did experiments distinguish pruritus with a "pricking quality" from that with a "burning quality. " 19 These experiments separated pruritus from touch, but still suggested that the two types of pruritus (epicritic and protopathic) corresponded to the two types of pain (epicritic and protopathic) and that epicritic (sharp, well-defined) pruritus and pain followed myelinated nerve fibers, whereas protopathic (diffuse, slow) pruritus and pain followed unmyelinated nerve fibers. A second major theory on cutaneous sensation is the pattern theory. This theory is diametrically opposed to the specificity theory. It states that cutaneous stimulation of nonspecific receptors is carried on nonspecific afferent nerve fibers to the brain. The brain recognizes the pattern of nerve impulses as a learned sensation, such as touch, pruritus, or pain. This theory is based on studies that showed no qualitative differences found in a variety of afferent nerve fibers when different cutaneous stimuli were applied. Therefore, it was surmised that the brain must be capable of distinguishing specific cutaneous sensations based on the characteristic pattern of stimulation it received. 36 This pattern was defined as the temporal and spatial relations of the nervous impulses. Probably there are portions of both theories that are correct. Gate Control Theory The gate control theory of pain was proposed in 1965. 32 It stated that the cells of the substantia gelatinosa of the dorsal horn of the spinal cord act as a swinging gate to dampen or accentuate afferent nerve patterns from large and small nerve fibers before they stimulate central transmission cells in the dorsal horn. These central transmission cells then activate nerve fibers to cause stimulation of an action system that is responsible for pain perception and response of the individual. It also states that the pattern of nerve impulses influences various parts of the brain to modulate the gate
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control system. Although this theory is quite complex, suffice it to say that the substantia gelatinosa cells modify afferent impulses from peripheral fibers to central cells. Central factors such as anxiety, previous experiences, boredom, or competing cutaneous sensations may act as a check and balance system on the substantia gelatinosa cells to either reduce or amplify the sensations of pain or pruritus. 12• 14• 31 This helps explain why pruritus often is perceived as being more intense at night, because other sensory input is low. The gate control theory was proposed to explain pain sensation, but the general concept of gating also has been accepted to explain pruritus. MEDIATORS It is not known whether a final common mediator of all pnuitus exists. Histamine has been suggested as a final mediator, but intradermal reactions take 10 to 50 seconds to cause pruritus, which does not support this idea. 25• 31 This latency may be due to slow accumulations of cyclic AMP. 25
Histamine Histamine is the first recognized pruritogen25 and is thought of as the classic mediator of pruritus. 31 Histamine is produced by mast cells in the dermis and stored in cytoplasmic granules in the mast cells. 22 As was mentioned earlier, intradermal injections of histamine cause pruritus, particularly if injected at the level of the dermoepidermal junction. 25 A deep injection of histamine will cause pain, especially if given in relatively large doses. 12 Intravenous injections of histamine will cause flushing, headaches, and edema but not pruritus. Single intradermal injections of histamine cause wheal formation and axonal flare in addition to pruritus. Following intradermal injections of histamine, it has been shown that vasodilatation (with its accompanying erythema) and increased vascular permeability (with the clinically perceived wheal) are influep.ced by H 1 and H2 receptors. 30 Itch and axon flare, however, only involve receptors of the H 1 type. Histamine acts on leukocyte H 2 receptors to inhibit additional histamine release. H 2 blockers reduce this negative-feedback effect. Also, H2 blockers inhibit the histamine degrading enzyme N-methyltransferase and therefore may actually exacerbate pruritus. 21 This helps explain why H 2 blockers (such as cimetidine and ranitidine) are of no value in the treatment of pruritus, and why H 1 blockers (the "classic" antihistamines) are only partially effective . In man, an age-related change occurs in that less pruritus is perceived in people more than 50 years old, even though the objective changes (wheal and flare) remain constant. 9 This has not been reported to occur in dogs and cats. It has been suggested that central sedation is more important than H 1 receptor antagonism for antipruritic effects in nonurticar'ial dermatoses. 27 However, in diseases in which wheal formation occurs due to histamine release, the H 1 blockers are effective. Because most patients with chronic pruritus respond poorly to antihistamines and do not show classic histamineinduced changes (wheal and flare), histamine probably is not the primary mediator of pruritus in these patients. 38
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Proteases, Peptides, and Cowhage Some of the earliest research on pruritus involved the use of cowhage as a pruritogen. 19· 25· 31· 33• 35 Cowhage is a legume, Mucuna pruriens, which has barbed spicules that act as a protective cover for the bean pods. 25 Cowhage was first described in English in 1688, although its pruritic properties were well known much earlier by natives. Cowhage grows in the tropics, including South America, Africa, India, and Central America. The name "cowhage" is thought to be a poor translation of the Hindu word "kiwach," which means "bad rubbing. "25 In the late 1700s, it was noted that boiling the spicules eliminated their pruritogenic properties. It was not until 1955, however, that Shelly and Arthur showed that the pruritus was due to the endopeptidase mucunain, and not to the mechanical trauma from the barbed spicules. 34 If the spicule was placed superficially, itching could be elicited without the development of erythema or wheals. Intradermal insertion of cowhage spicules produced pruritus in 15 to 30 seconds. Co~hage can cause pruritus in skin depleted of its histamine. These findings suggest that mucunain is not the final mediator of pruritus and that histamine was not involved with the pruritus from spicules. Other proteases have also been suggested as pruritic agents, which is an attractive hypothesis in light of all of the proteases released from the skin and blood during the acute phase of inflammation. Suggested endogenous proteases include trypsin, chymotrypsin, and fibrinolysin . Exogenous proteases such as ficin, papain, and streptokinase also induce itch. Some proteases can be boiled to destroy their proteolytic activity; however, their pruritogenic properties remain unchanged. Proteases are potent histamine liberators, and it is likely their pruritic properties are due to this effect, rather than mechanisms independent of histamine. 15 Substance P Substance P is an undecapeptide neurotransmitter that has been identified in the afferent neurons of cat and rat skin, where it produces vasodilatation and increased vascular permeability. 26 Substance P is also found in the brain and spinal cord and in the nerve supply to the gastrointestinal tract. 29 Two distinct subclasses of substance P receptors have been proposed. 39 Substance P is a pote nt histamine liberator, and its effects are inhibited by H 1 antihistamines, suggesting that most or all of its effects are indirect. Serotonin, bradykinin, and lysylbradykinin may also play a role in the genesis of pruritus. 31 • 38 Opiate Peptides Opioid peptides such as leucine enkephalin (leu-enkephalin) and methionine enkephalin (met-enkephalin) are found throughout the central and peripheral nervous systems. Systemic administration of morphine relieves pain but causes pruritus by acting centrally on opioid receptors. Morphine will potentiate the pruritus evoked by histamine . 16 · Naloxone hydrochloride (Narcan) is a selective opiate antagonist that has been shown to inhibit the central perception of pruritus experimentally induced by histamine. 5 Peripheral effects of naloxone on pruritus are more contradictory, in that naloxone failed to reduce the duration of the itch
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response. 16 Currently, most evidence implies that opioid peptides in the central nervous system act as mediators in the perception of pruritus. Opiate antagonists may play a much greater role in the control of pruritus in the future. Prostaglandins In normal, uninflamed skin, prostaglandins are present in insignificant amounts. In the presence of excess arachidonic acid (substrate), prostaglandins are rapidly synthesized in the skin. 20 This suggests that the presence of prostaglandins in inflammatory skin diseases is due to local biosynthesis rather than release from existing stores. Increases in arachidonic acid .concentrations during inflammation probably provide the stimulus for this biosynthesis. In arachidonic acid metabolism, a variety of pro-inflammatory agents are produced. The lipoxygenase pathway results in the formation of leukotrienes, whereas prostaglqndins are produced in the cyclooxygenase pathway of arachidonic acid metabolism . . Prostaglandin E 1 (PGE 1) is unable to cause pruritus by itself, 22 but it significantly lowers the itch threshold in human skin in vivo to pruritus that has been experimentally induced by histamine and papain. 28 Prostaglandin E 2 and PGH 2 (an unstable prostaglandin endoperoxide that is formed as an intermediate metabolite in the arachidonic acid pathway) are capable of producing pruritus, although PGE 2 is more potent. When given with histamine, both PGE 2 and PGH 2 produced a greater degree of pruritus and flare than can be explained by their cumulative effects. This suggests that prostaglandins and their intermediates may potentiate the pruritus and flare reaction in inflammatory skin diseases. 8 • 23 Prostaglandin E 2 and PG F 2 alpha biosynthesis in skin is inhibited by flucinolone and hydrocortisone, although the inhibition of PGE 2 by hydrocortisone is not statistically significant. 20 This indicates that at least some of the anti-inflammatory properties of corticosteroids are due to antiprostaglandin effects. Leukotrienes Most experimental work with leukotrienes is aimed at defining local inflammatory changes with little information available regarding their role in pruritus or pain. 8 • 37 Leukotriene (LT) C4, 0 4 , and E 4 are components of slow-reacting substance of anaphylaxis (SRS-A) and cause formation of erythema and wheals when injected intradermally. 37 Dermal capillaries and superficial and deep venules showed dilatation and endothelial cell activation, whereas arterioles only became dilated. This erythema and whealing are dose-related. Leukotriene 0 4 and LTE 4 may cause transient burning on injection but not pruritus. Leukotriene B4 (LTB4 ) is one of the most potent neutrophil chemoattractants known. In one of four subjects, intradermal injection of LTB4 caused persistent pruritus. 8 Prostaglandin 0 2 is the primary product in human mast cell arachidonic acid metabolism. By itself, PGD 2 causes intradermal wheal and erythema formation with little neutrophil accumulation. When injected intradermally together, PGD2 and LTB4 cause tenderness and a much greater degree of edema and accumulation than can be explained by their cumulative effects. This suggests that PGD 2 and LTB4 act in synergy37 as mediators of inflammation. Currently,
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however, there is no evidence that leukotrienes are directly involved with pruritus. 12
PERCEPTION OF PRURITUS Once pruritus has been initiated, there are numerous central factors and adjunct influences on the perception of pruritus. Dry skin (xerosis) is frequently seen in environments with low ambient humidity, and will lower the pruritic threshold. In man, various anatomic locations, such as the wrist and face, have a low threshold for itching. 22 Age also affects pruritus. Intradermal injections of histamine will produce consistent erythema and wheal formation, but the degree of pruritus perceived will lessen as people age.9 Whether this phenomenon occurs in dogs and cats is unknown. A pinprick near a pruritic focus or in the same dermatome will at least temporarily abolish the itch. 4 • 25 Likewise, cold, heat, ultraviolet radiation, and vibration will also diminish . pruritus. Experimentally induced itch is abolished in human patients with atopic dermatitis by cooling the skin surface. 17 Heating the skin surface will aggravate this same itch in one third of the patients and abolish or diminish the pruritus in two thirds of these patients. According to the gate control theory, these competing cutaneous sensations may act to reduce the cognizant perception of the itch spot via spinal modulation of afferent stimuli. Anxiety, excitement, and heightened states of alertness may have selective enhancement or suppression of the perception of pruritus. 25 · Acupuncture has also been shown to influence pruritus. Patients with experimental histamine-induced itch and flare were treated with acupuncture, were treated with application of acupuncture needles near acupuncture points (pseudoacupuncture), or were not given any treatment, 15 minutes prior to histamine injection. 3 Acupuncture had little effect on the onset time of pruritus or on the maximum itch intensity. However, acupuncture had a statistically significant dampening effect on the size of maximal flare, on the duration of itch, and on the overall (cumulative) itch perceived. Pseudoacupuncture had only minimal effect, suggesting that the acupuncture points are rather specific. However, it must be noted that the induced pruritus was mild and that severe pruritus may not respond in a similar manner.
SCRATCHING The exact relationship between itch and scratch is unknown. Why does scratching relieve itching? Scratching in response to itch is a spinal reflex, although it is modified by input from higher centers, including the frontal cortex. 7 It has been proposed that scratching substitutes pain for itch. This is unlikely, because the slight pain from several pinpricks will abolish itch in adjacent areas of skin for up to 45 seconds, even though the pain disappears within 15 seconds. Another explanation suggests that scrat~hing
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damages sensory nerve endings and that the delay in the return of pruritus may be the time required for regeneration of these endings. 22 Scratching patterns show that the length of the scratch stroke decreases as the pruritus progresses distally on the extremities-that is, scratch strokes are shortest on the fingers and toes, and longest on the proximal extremities and trunk. 10 It was suggested that this was due to the concentration of tactile receptors, because tactile receptors are more concentrated on the fingers and toes, and less concentrated on the proximal extremities and trunk. Scratch strokes need to be longer on the trunk in order to adequately stimulate tactile receptors, but they are short on the fingers, where tactile receptors are close together. 10 Referred itch is an odd phenomenon present in approximately 20 per cent of people. 13 It is a sensation of pruritus that occurs somewhere else on the body when a primary itch is scratched. When an itch sensation occurs, this referred itch is ipsilateral to the primary itch, well-localized, shortlived, and reproducible. 13 Scratching the legs and trunk most frequently produced referred itch, whereas the face, palms, and soles rarely produced referred itch. The referred itch usually occurs at a higher segmental level in the nervous system, when compared to the primary itch site. If symmetr;ical sites on each side of the body are stimulated to itch, the referred itch sites are not symmetrical. Stimulating identical sites on different individuals does not result in identical sites of referred itch, indicating that this is an individual response. This is an interesting concept to consider as a plausible explanation of severe generalized pruritus in an allergic dog. Paroxysmal pruritus is a controversial topic in human dermatology that explains a type of severe pruritus that results in self-mutilation. Arnold suggests that this itching originates in the central nervous system as a result of a strong emotional state (that is, anger, guilt, resentment). 1 This misplaced release of energy results in bursts or paroxysms of severe itching. There is a concomitant extraordinary elevation in the pain threshold to this site of pruritus. Rather than feeling intense pain, these patients report feelings of tremendously gratifYing pleasure. Once pain is finally felt, the itching immediately ceases and does not return until the damaged skin heals. This severe pruritus has not been reported in the veterinary literature; however, it may partially explain why some dogs and cats scratch or chew their skin to cause severe damage. The author is aware of a male Great Dane with probable cauda equina syndrome that self-amputated the distal half of its tail by chewing through it at the midpoint. One can only speculate that there were both a severe pruritus and a tre mendous increase in pain tolerance .
SUMMARY In spite of the research that has been performed , pruritus remains a poorly understood sensation. It is important to remember that the majority of information presented here is derived from observations of human
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subjects. One can only speculate as to how much of this information can be extrapolated to pruritus in animals. Pruritus is closely intertwined with pain and touch. Pain and pruritus sensations are carried on A delta and C fibers, ascend on the lateral spinothalamic tract, and terminate in various brain centers, including the thalamus and the cortex. The gate control theory of pain and pruritus describes the substantia gelatinosa cells as "swinging gates" to modify peripheral input and result in stimulation of higher centers. Central factors reduce or amplify the perception of these cutaneous sensations. Histamine is the classic mediator of pruritus, although it is still unknown whether a final common mediator of pruritus exists. Numerous other medtators include proteases, peptides, substance P, opiate peptides, prostaglandins, and leukotrienes. These may have pruritic properties directly, or may act as histamine liberators to cause pruritus.
REFERENCES 1. Arnold HL: Paroxysmal pruritus: Its clinical characterization and a hypothesis of its pathogenesis. J Am Acad Dermatol 11:322, 1984 2. Ayres S: The fine art of scratching. JAm Med Assoc 189:1003, 1964 3. Bellgrade MJ, Solomon LM, Lichter EA: Effect of acupuncture on experimentally induced itch. Acta Derm Venereol (Stockh) 64:129, 1984 4. Bernhard JD: In Fitzpatrick TB, Eisen AZ, Wolf K, et al (eds): Dermatology in General Medicine. Edition 3. New York, McGraw-Hill, 1987 5. Bernstein JE, Swift RM, Soltain K, et al: Antipruritic effect of an opiate antagonist, naloxone hydrochloride. J Invest Dermatol 78:82, 1982 6. Bickford RG: Experiments relating to itch sensation, its peripheral mechanism and central pathways. Clin Sci 3:377, 1938 7. Bradford FK: Ablations of frontal cortex in cats with special reference to enhancement of the scratch reflex. J Neurophysiol 2:192, 1939 8. Camp RDR, Coutts AA, Greaves MW, et al: Responses of human skin to intradermal injection of leukotrienes C,, D, , and B,. Br J Pharmacol 80:497, 1983 9. Cormia FE: Experimental histamine pruritus. J Invest Dermatol 19:21, 1952 10. Cornblett T: Scratching patterns. J Invest Dermatol 20:105, 1953 11. de Lahunta A: Veterinary Ne uroanatomy and Clinical Neurology. Edition 2. Philadelphia, WB Saunders Co, 1983 12. Denman ST: A review of pruritus. J Am Acad Dermatol 14:375, 1986 13. Evans PR: Referred itch (mitempfindungen). Br Med J 2:839, 1976 14. Fjellen B, Hagermark 0: Transcutaneous nerve stimulation and itching. Acta Dermatol 58:131, 1978 15. Fjellen B, Hagermark 0: Studies on pruritogenic and histamine-releasing effects of some putative peptide neurotransmitters. Acta Dermatol 61:245, 1981 16. Fjellen B, Hagermark 0: The influence of the opiate antagonist naloxone on experimental pruritus. Acta Derm Venereol (Stockh) 64:73, 1984 17. Fruhostorfer H, Hermanns M, Latzke L: The effects of thermal stimulation on clinical and experimental itch. Pain 24:259, 1986 18. Friedman R: Emperor's itch: Legend concerning Napoleon's affiiction with scabies. Bull Hist Med 8:949, 1940 19. Graham DT, Goodell H, Wolff H : Neural mechanisms involved in itch, "itchy skin" and tickle sensations. J Clin Invest 30:37, 1951 20. Greaves MW, McDonald-Gibson W: Inhibition of prostaglandin biosynthesis by corticosteroids. Br Med J 2:83, 1972 21. Greaves MW: H2 receptor antagonists and delayed hypersensitivity. Lancet 1:880, 1978 22. Greaves MW: In Fitzpatrick TB, Eisen AZ, Wolf K, et al (eds): Dermatology in General Medicine. Edition 3. New York, McGraw-Hill, 1987
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23. Hagermark 0: Potentiation of itch and Hare responses in human skin by PGE2 and PGH 2 and a prostaglandin endoperoxide analog. J Invest Dermatol 69:527, 1977 24. Hardy JD, Wolf HG, Goodell H: Experimental evidence on the nature of cutaneous hyperalgesia. J Clin Invest 29:115, 1950 25. Herndon JH: Itching: The pathophysiology of pruritus. lnt J Dermatol 14:465, 1975 26. Jorizzo JL, Coutts AA, Eady RAJ, et al: Vascular responses of human skin to injection of substance P and mechanism of action. Eur J Pharmacol 87:67, 1983 27. Krause L, Shuster S: Mechanism of action of antipruritic drugs. Br Med J 287:119, 1983 28. Lovell CR, Burton PA, Duncan EHL, et al: Prostaglandins and pruritus. Br J Dermatol ...g4:273, 1976 29. Luttgen PJ: An outline of neurotransmitters and neurotransmission. Part II. Function and dysfunction. J Am Anim Hosp Assoc 23:663, 1987 30. Marks R, Greaves MW: Vascular reactions to histamine and compound 48/80 in human skin: Suppression by a histamine H2 blocking agent. Br J Clin Pharmacol 4:367, 1977 31. Martin J: Pruritus. lnt J Dermatol 24:634, 1985 32. Melzack R, Wall PO: Pain mechanisms: A new theory. Science 150:971, 1965 33. Rothman S: In Montagna W (ed): Advances in Biology of the Skin. Volume I. Oxford, Pergamon Press, 1960 34. Shelly WB, Arthur RP: Studies on cowhage (Mucuna pruriens) and its pruritogenic proteinase, mucunain. Arch Dermatol 72:399, 1955 35. Shelly WB, Arthur RP: The neurohistology and neurophysiology of the itch sensation in man. Arch Dermatol 76:296, 1957 36. Sinclair DC: Cutaneous sensation and the doctrine of specific energy. Brain 78:584, 1955 37. Soter NA, Lewis RA, Corey EJ, et al: Local effects of synthetic leukotrienes (LTC,, LTD,, LTE 4, and LTB,) in human skin. J Invest Dermatol 80:115, 1983 38. Tuckett RP, Denman ST, Chapman CR, et al: Pruritus, cutaneous pain, and eccrine gland and sweating disorders. JAm Acad Dermatol11:1000, 1984 39. Watson SP, Sandberg BEB, Hanley MR, et al: Tissue selectivity of substance P alkyl esters: Suggesting multiple receptors. Eur J Pharmacol87:77, 1983 40. Winkelmann RK: Pharmacologic control of pruritus. Med Clin North Am 66:1119, 1982 Department of Clinical Studies School of Veterinary Medicine University of Pennsylvania 3850 Spruce Street Philadelphia, Pennsylvania 19104