Epinephrine Induction of White Hair in Aci Rats*

Vol. 53, No.2 Printed in U.S.A.

THE JOURNAl, OP INVESTIGATIVE DERMATOLOGY

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1969 by The Williams & Wilkins Co.

EPINEPHRINE INDUCTION OF WHITE HAIR IN ACI RATS* WALTER B. SHELLEY, MD. AND

SVEN OilMAN, M.D. ABSTRACT A single injection of epinephrine into an area of skin of ACI rats from which pigmented hairs have been plucked leads regularly to a regrowth of completely non-pigmented hairs. The injection is effective when given any time during the 10-day anagen cycle after plucking. The longer the interval between plucking and the injection, the greater the delay in new white hair growth. The conclusion is drawn that the new white hairs reflect selective damage or destruction of the hair bulb melanocytes following the intense vasoconstriction induced by epinephrine.

Although neuro-humoral factors have been

plucked areas of the leg where the repeated in-

considered in the pathogenesis of graying jections were made (4). The epinephrine was administered both subcutaneously in aqueous solution and intramuscularly with an oily suspension in each instance in a dose of 0.1 mg

of hair and clinicians have recorded hair turning white from fright, little experimental data appears in the literature (1, 2). We were accordingly intrigued to come upon a rather hidden observation of Findlay and Jenkinson that the single local injection of epinephrine into the skin of Ayrshire calves turned their normally brown hair white in the exact area of vasoconstriction (3). The change in color was dramatic in that the transition from brown to white in the hair shaft was sharply defined. Significantly the depigmentation was limited to the hair; the brown epidermis remained fully pigmented.

twice daily. At times small necrotic areas of skin were noted at the site of repeated injection. White hairs appeared in the hind legs of

the rats after 56 injections of epinephrine. rhitening of hairs was never noted except over the injection sites and Mohn ventured no view

as to its nature, except to point out that the effect was not due to mechanical injury since the animals receiving control vehicle injections rarely grew white hairs.

No clear role for epinephrine in melanin synthesis has been discerned, Yet, Stubble-

The loss of hair pigment was complete and persisted for months. It occurred only after injection of epinephrine in a concentration of 1/1000; more dilute solutions were without effect. The loss of hair color was interpreted by Findlay and Jenkinson as attributable to

field, Escue and Utt (5) found that epinephrine did aggregate preformed melanin granules in tissue culture melanocytes derived from both mouse skin and melanomas. Such aggregation

selective destruction of the melanocyte by the did not occur in surviving dermal melanointense vasoconstriction. Concomitant degen- cytes from mice (6) and the epidermal melanoerative changes were noted in the sweat gland cytes are refractory to hormones which regularly evoke lightening of amphibian skin (7).

epithelium.

In the present study we have attempted to

A careful search of the literature revealed

only one other incidental report of the effect of find a model for further study of the local deepinephrine on hair pigmentation. In this study velopment of achromotrichia in areas injected Mohn recorded that 37 black rats injected daily with epinephrine.

with epinephrine for more than 4 weeks

MATERIALS AND METHODS

showed a regrowth of white hair locally in Supported by a John A. Hartford Foundation, Inc. grant. Received February 24, 1969; accepted for publication March 11, 1969.

Studies were done on thirty-two C57 BL/6 black mice, thirteen Brown-Norway rats, and fiftyseven ACI rats (Microbiological Associates, Inc.,

Bethesda, Maryland). The ACI strain was repre-

sented by inbred females, 100—150 grams in size. versity of Pennsylvania School of Medicine, Phila- It has an agouti brown-black pigmented hair popu-

* From the Department of Dermatology, Uni-

delphia, Pennsylvania 19104.

lation on the back, whereas the ventral hair is

155

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white. Pigmented hairs were manually plucked from a circular area on the back. One-tenth milliliter of epinephrine solution (Parke-Davis) in 1/1000 strength (or serial dilutions thereof in sterile saline) was injected intradermally in the center of the epilated skin site. Control injections consisted of 0.9% sodium chloride, 0.1% sodium

given to various animals on every day, I

bisulfite in distilled water. A single injection gen-

All regrew pigmented hairs. By contrast, all of the ACT rats regrew white hair in plucked areas in which epinephrine was

erally was given esch animal, but litter mates were injected on sequential days to study time relationships of the plucking, injection and regrowth. Readings of the skin color, skin appearance, hair regrowth pattern, color and density were made three times a week for six months.

through 20, following plucking. In some C57 BL/6 animals two sequential injections were made, i.e., days 0 and 6, 1 and 7, 2 and 8, 3 and 9, 4 and 10, 5 and 11, 6 and 12, 7 and 13, 8 and 14, 9 and 15, 10 and 16, 15 and 21, 20 and 26.

injected intradermally (Fig. 1). In a typical

experiment, the hairs were plucked, and 0.1 ml Representative biopsies were also taken for histo- of 10-' epinephrine was injected on day 4. This was followed days later by crust formation at logic examination. Additional studies were made following the the injection site. The crust remained for over injection of mecholyl and nor-epinephrine, as well as local freezing. RESULTS

Nene ef the Brown-Norway rats nor the C57 BL/6 black mice showed any white hair formation following plucking and a single local intradermal injection of epinephrine 10' (0.1 ml for

two weeks, to be followed by a luxuriant growth of new white hairs by the third to fourth week. Injecting the epinephrine on the day after plucking shortened the interval to regrowth of

white hairs, whereas the interval could be lengthened by waiting until 10 days after plucking before injecting the epinephrine. Two injections in the same site a week apart also de-

rats, 0.03 ml for mice). The injections were layed regrowth but the same white hair appeared.

Reducing the concentration to 1/2000 made no change, but at 1/5000 the crusting was not as thick and some of the new hairs were pigmented. At a level of 1/10,000 the injection of 0.1 ml was without effect, but the whitening could be achieved by simply injecting a larger quantity, 0.25, 0.50 or 1.00 ml. At a concentration of 1/100,000 a single injection of epiriephrine was followed by the regrowth of brown pigmented hairs, despite the injection of volumes up to 1.0 ml. Injection of epinephrine into unplucked skin had no effect on the color of the hair in situ, but in some instances the subsequent hair population was depigmented. Finally plucking alone was not followed by regrowth of depigmented hairs.

Norcpinephrine (0.1 ml, 1/1000, 1/5000, 1/10,000) had no consistent effect on the repig-

mentation cycle in eight rats. It did produce

crusting, but it was significantly less than that following epincphrine, and only an occasional animal showed depigmentation of hairs. Mecholyl (0.5 ml, 1/1000) was likewise without effect. Similarly the bisulfite vehicle control injections (up to 1 ml) were followed by regrowth of brown hair. Freezing the skin with Pie. 1. White heir growth four weeks following dry ice for 20 and 40 seconds did induce crusting injection of epinephrine (1 ml — 10-i) into area of the skin, but this was followed by rcgrowth 4 days after plucking an oval area of brown hairs on the back of an ACT rat.

of fully pigmented hairs.

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laboratory animal. It should be of value for the investigation of follicular melanocyte repopulation. Further studies of the effect of repeated DISCUSSION injections of low concentrations of epinephrine, Is the public right in believing fright turns its analogues, synergists and antagonists, should

Histologically the white zones showed a preponderance of melanin free hairs.

hair white? It is this question that makes the be done. In this regard it is significant that study of the effect of any stress hormone on hair Munan (19) found that subcutaneous injec-

tions of "partially oxidized" adrenalin induced local alopecia iii black rats, followed by local centration as low as 1/10,000 induced the regrowth of gray hair which remained permagrowth of nonpigniented hairs in brown AOl nently depigmented. His report was prelimirats. This is in agreement with the earlier find- nary, and he did not give details of dosage nor ing of Findlay and Jenkinson that epinephrine did he study the effect of adrenalin itself. induced white hair growth in Ayrshire calves REFERENCES and the observation of Mohn that multiple in1. Lerner, A. B.: Vitiligo. J. Invest. Derm., 32: 285, 1959. jections of epinephrine in the leg of black rats A. J.: On sudden or rapid whitening over a period of months was followed by local 2. Ephraim, of the hair. Arch. Derm., 79: 228, 1959. depigmeiitation of new hair. Although there 3. Findlay, J. D. and Jenkinson, D. M.: Sweat gland function in the Ayrshire calf. Research were no clues as to the possible mechanism of in Vet. Science, 5: 109, 1964. this striking effect from a study of the modes 4. Mohn, M. P.: The effects of different hormonal states on the growth of hair in rats, of action of other hormones on hair (8, 0), one The Biology of Hair Growth. Eds., Monmight surmise that the epinephrine was acting tagna, W. and Ellis, R. A., Academic Press, in a chemically specific fashion, or in a nonNew York, 1958. specific damaging way as suspected by Findlay 5. Stubblefield, E., Escue, R. B. and Utt, J.: Melanin mobilization in pigment cells in and Jenkinson (3). Interestingly, norepinephrine the mouse. Science, 126: 28, 1957. did not induce the same effect as epinephrine. 6. Reams, W. M., Shervette, R. E. and Dorman, W. H.: Refractoriness of mouse dermal To ignore basic genetic and aging determimelanocytes to hormones. J. Invest. Derm., nants, hair depigmentation from the chemical 50: 338, 1968. 7. Klaus, S. N. and Snell, H. S.: The responses of standpoint may reflect either copper or vitamin mammalian melanocytes in culture to hordeficiencies, or poisoning with phenyl thiourea, mones. J. Invest. Derm., 48: 352, 1967. molybdenum, or chioroquin (10). The present 8. Downes, A. M. and Wallace, A. L. C.: Local effects on wool growth of intradermal injections story as we have seen it tends to be different of hormones, Biology of the Skzn and Hair since epinephrine fails to act in very low conGrowth. Eds., Lyne, A. G. and Short, B. F., centrations or at a distance, produces enough Elsevier Publishing Co., New York, 1965. tissue necrosis to induce crust formation, and 9. Johnson, E.: Growth and replacement of hair, Rodents in Comparative Physiology and Painduces an irreversible effect in that subsequent thology of the Skin. Eds., Rook, A. J. and hairs coming from the same follicle continue Walton, G. S., F. A. Davis, Co., Philadelphia, pigmentation intriguing. We found that a single intradermal injection of epinephrine in a con-

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