Experimental evidence shows that histamine is liberated when the upper layers of the skin are stimulated in the threshold range although no gross or microscopic evidence of tissue damage is demonstrable. A histamine-like substance is recoverable from the anterior chamber of the rabbit's eye on electrical stimulation of the cornea. This substance is liberated in direct proportion to the intensity of the stimulus. Histamine when injected intradermally or applied to the denuded skin (less epidermis and some cutis) or cornea causes pain. That the substance liberated is most likely histamine was shown by its action on the intestinal strip of the guinea pig, which action was not effaced by adding atropine to the bath; by its heat stability, its neutralization by histaminase and its dialysability through cellophane membranes, and by the fact that thymoxyethyldiethylamine, which appears to be a specific antagonist to histamine, neutralizes the action of the diffusates of stimulated skin and when injected subcutaneously or rectally abolishes generally the pain responses to pinching, pricking and cutting, and lowers the electrical threshold of the skin markedly without affecting the somatic sensory nerve trunks.

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