172 W. J. CROZIER ; 
seems to me) quite unwarranted objection. According to a 
conception first formally advanced by Botezat (’10) and later 
applied by Parker (712) to the general chemical irritability of 
moist surfaces in vertebrates, the stimulation of epithelial free 
nerve terminals is accomplished secondarily through the activity 
of substances diffusing from the more external epithelial cells 
(some of which may be supposed to be in a special receptive state, 
although this is not necessary) to deeper parts. There is ob- 
viously no necessity that the nerve terminals concerned be situ- 
ated near the surface immediately exposed to the activating agent. 
The cells primarily activated by acid or alkali in the ‘common 
chemical sense’ experiments are undoubtedly those of the very 
outermost layer of the skin. A study of the conditions of chemi- 
cal activation in primary receptors (of the earthworm) shows, 
or seems to show, that a chemical reaction occurs between the 
activating agent and some receptor constituent.° 
This means that the acid or other agent stimulates after union 
with, or penetration of, the surface of the superficial cells. The 
acid or other substance does not act directly upon deeper layers 
of the skin, for the good and sufficient reason that the stimula- 
tion time is utterly inadequate for any such process, even though 
the changed condition in the cell primarily affected can obviously 
be transmitted from cell to cell through the whole depth of the 
epidermis in a very brief time. The fact that one small area 
of the skin may be excited repeatedly by acid or by alkali shows 
that no destructive action is wrought by these excitants (within 
reasonable limits of concentration). 
It is becoming more and more necessary to recognize that re- 
ceptor organs depend for their differential irritability upon the 
possession of specific substances which enter into excitation re- 
actions. There is reason to suppose that in mechanical stimu- 
lation surfaces (intracellular, intercellular, or both) are tempo- 
5 Some of the results of this investigation are in course of publication. 
6 This primary effect may or may not be an increase in cell permeability, but 
it undoubtedly does involve an alteration in the relations between ions at the 
surfaces of the stimulated cells; hence the violent stimulating effect of distilled 
water under certain circumstances, as Loeb long ago found in the case of the 
frog’s foot. 
