British Journal of Dermatology {1976) 94, 273.
Prostaglandins and pruritus' C.R.LOVELL, PATRICIA A.BURTON, ETHEL H.L.DUNCANf AND J.L.BURTON Department of Dermatology, Bristol Royal Infirmary, and t Department of Community Health, University of Bristol, Bristol Accepted for publication 4 July 1975
SUMMARY
We have found that pretreatment of human skin with prostaglandin Ej signiflcantly lowers the threshold of human skin to itching evoked by both histamine and papain. Prostaglandins may thus potentiate pruritus in inflammatory skin disease, presumably by a non-specific effect on nerve-endings.
The cause of itching in inflammatory skin disease is unknown. Prostaglandins are known to be present in increased amounts in inflamed skin (Angaard, Arturson & Jonsson, 1970; Greaves & Sondergaard, 1970; Greaves, Sondergaard & McDonald-Gibson, 1971; Arturson, Hamberg & Jonsson, 1973), and Greaves & McDonald-Gibson (1973) have produced evidence that a prostaglandin may contribute to pruritus by lowering the itch threshold of skin. We have now tested this idea further by determining the threshold to histamine-evoked and papain-evoked itching in normal skin and in skin pre-treated with prostaglandin.
PATIENTS AND METHODS
We studied ten male and ten female subjects (age range 17-65 years) who were either volunteer members of the medical staff or patients with localized non-inflammatory skin disease such as warts. None of the subjects was taking antipruritic or anti-inflammatory drugs at the time of the study. The efFect of prostaglandin Ej on the threshold of the itch induced by histamine and papain was studied in the following way. Both forearms were washed and dried, and four i cm^ areas were lightly scarifled on the flexor surface of each forearm, care being taken to avoid any bleeding. A i cm^ piece of gauze soaked in prostaglandin E, in a concentration of i /(g/ml was placed on two scarified areas on each forearm and left for 30 min. As control sites the other two scarified areas on each forearm were treated with gauze soaked in phosphate-buffered saline. The allocation of prostaglandin or saline to the four sites on the right arm was randomized and the opposite allocation was made to the four sites on the left arm, so that symmetrical paired comparisons between prostaglandin and saline-treated areas could be made. The itch threshold for histamine was then determined in two of the paired areas, * Based on a paper read at the 1975 Meeting of the Investigative Group of the B.A.D. 273
C.R.Lovell et al.
274
and the threshold for papain was determined in the other two paired areas. The test solutions used were histamine acid phosphate (i mg/ml, expressed as histamine base) and twice crystallized papain suspension containing 16-40 BAEE units/mg (Sigma London Chemical Co. Ltd.). Five minutes after removal of the gauze, o-i ml of histamine diluted i : 1000 was placed on the scarified skin and left for 2 min. This was followed at 2 min intervals after drying by increasing concentrations of histamine (i: 500, 1:2oo, I: IOO, 1150, i lao, and i : 10) until itching occurred. The itch threshold was recorded as the lowest concentration of histamine which produced itching. The itch threshold for papain was similarly determined, starting with a i in 500 dilution of the papain solution and progressing by geometric increments to a i in 5 dilution. In each patient two paired comparisons of saline-treated and prostaglandin-treated sites were thus made for both histamine and papain and both observer and patient were unaware of the allocated treatment.
RESULTS
In the concentration used prostaglandin E^ did not by itself cause itching after application to scarified skin. We found the results expressed as a dilution to be log-normal. To normalize the distribution, therefore, we have expressed oiu: data as the logarithm of the lowest concentration which produced itching (Fig. i a and b). These results show that, although there is a wide scatter, there is a ten-
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FIGURE I. Histamine (a) and papain (b) thresholds in skin pretreated with normal saline and with prostaglandin. Each result is expressed as the log of the first dilution which produced itching, and there are two results from every patient in each figure.
dency for the prostaglandin-treated side to have a lower threshold for pruritus evoked both by histamine and papain. To enable the statistical significance of this change to be assessed we calculated the mean log ratio (dilution for prostaglandin side/saline side) of the two matched pairs of tests for each patient, for both histamine and papain. The mean of these mean log ratios for the twenty patients was O-IOOI + OO45 for histamine and o-iioo+oo5O for papain. That is, on average the concentration of histamine on the prostaglandin-treated side was o-8o times that on the saline-treated side, and for papain the figure was 078. Both the mean log ratios were significantly greater than zero (t = 2-224 and 2-200 respectively, d.f. = 19, P
Prostaglandins and pruritus' C.R.LOVELL, PATRICIA A.BURTON, ETHEL H.L.DUNCANf AND J.L.BURTON Department of Dermatology, Bristol Royal Infirmary, and t Department of Community Health, University of Bristol, Bristol Accepted for publication 4 July 1975
SUMMARY
We have found that pretreatment of human skin with prostaglandin Ej signiflcantly lowers the threshold of human skin to itching evoked by both histamine and papain. Prostaglandins may thus potentiate pruritus in inflammatory skin disease, presumably by a non-specific effect on nerve-endings.
The cause of itching in inflammatory skin disease is unknown. Prostaglandins are known to be present in increased amounts in inflamed skin (Angaard, Arturson & Jonsson, 1970; Greaves & Sondergaard, 1970; Greaves, Sondergaard & McDonald-Gibson, 1971; Arturson, Hamberg & Jonsson, 1973), and Greaves & McDonald-Gibson (1973) have produced evidence that a prostaglandin may contribute to pruritus by lowering the itch threshold of skin. We have now tested this idea further by determining the threshold to histamine-evoked and papain-evoked itching in normal skin and in skin pre-treated with prostaglandin.
PATIENTS AND METHODS
We studied ten male and ten female subjects (age range 17-65 years) who were either volunteer members of the medical staff or patients with localized non-inflammatory skin disease such as warts. None of the subjects was taking antipruritic or anti-inflammatory drugs at the time of the study. The efFect of prostaglandin Ej on the threshold of the itch induced by histamine and papain was studied in the following way. Both forearms were washed and dried, and four i cm^ areas were lightly scarifled on the flexor surface of each forearm, care being taken to avoid any bleeding. A i cm^ piece of gauze soaked in prostaglandin E, in a concentration of i /(g/ml was placed on two scarified areas on each forearm and left for 30 min. As control sites the other two scarified areas on each forearm were treated with gauze soaked in phosphate-buffered saline. The allocation of prostaglandin or saline to the four sites on the right arm was randomized and the opposite allocation was made to the four sites on the left arm, so that symmetrical paired comparisons between prostaglandin and saline-treated areas could be made. The itch threshold for histamine was then determined in two of the paired areas, * Based on a paper read at the 1975 Meeting of the Investigative Group of the B.A.D. 273
C.R.Lovell et al.
274
and the threshold for papain was determined in the other two paired areas. The test solutions used were histamine acid phosphate (i mg/ml, expressed as histamine base) and twice crystallized papain suspension containing 16-40 BAEE units/mg (Sigma London Chemical Co. Ltd.). Five minutes after removal of the gauze, o-i ml of histamine diluted i : 1000 was placed on the scarified skin and left for 2 min. This was followed at 2 min intervals after drying by increasing concentrations of histamine (i: 500, 1:2oo, I: IOO, 1150, i lao, and i : 10) until itching occurred. The itch threshold was recorded as the lowest concentration of histamine which produced itching. The itch threshold for papain was similarly determined, starting with a i in 500 dilution of the papain solution and progressing by geometric increments to a i in 5 dilution. In each patient two paired comparisons of saline-treated and prostaglandin-treated sites were thus made for both histamine and papain and both observer and patient were unaware of the allocated treatment.
RESULTS
In the concentration used prostaglandin E^ did not by itself cause itching after application to scarified skin. We found the results expressed as a dilution to be log-normal. To normalize the distribution, therefore, we have expressed oiu: data as the logarithm of the lowest concentration which produced itching (Fig. i a and b). These results show that, although there is a wide scatter, there is a ten-
(o)
3-0 p
/
3-3 -
•
•
3-7 -
/
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A
2-3
*
•
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Log cone papain Saline
1
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3-0
I 1-0
I
2-7
I I 2-3 2-0 3-7
I 3-3
3-0
Log cone histamine Soline
FIGURE I. Histamine (a) and papain (b) thresholds in skin pretreated with normal saline and with prostaglandin. Each result is expressed as the log of the first dilution which produced itching, and there are two results from every patient in each figure.
dency for the prostaglandin-treated side to have a lower threshold for pruritus evoked both by histamine and papain. To enable the statistical significance of this change to be assessed we calculated the mean log ratio (dilution for prostaglandin side/saline side) of the two matched pairs of tests for each patient, for both histamine and papain. The mean of these mean log ratios for the twenty patients was O-IOOI + OO45 for histamine and o-iioo+oo5O for papain. That is, on average the concentration of histamine on the prostaglandin-treated side was o-8o times that on the saline-treated side, and for papain the figure was 078. Both the mean log ratios were significantly greater than zero (t = 2-224 and 2-200 respectively, d.f. = 19, P
