In vitro activity: Diphenhydramine blocks tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) sodium currents with K(d) values of 48 mM and 86 mM, respectively, at a holding potential of -80 mV. Diphenhydramine shifts the conductance-voltage curve for TTX-S sodium currents in the depolarizing direction but has little effect on that for TTX-R sodium currents. Diphenhydramine causes a shift of the steady-state inactivation curve for both types of sodium currents in the hyperpolarizing direction. Diphenhydramine produces a profound use-dependent block when the cells are repeatedly stimulated with high-frequency depolarizing pulses. Diphenhydramine induces apoptosis in a dose- and time-dependent manner in both CCRF-CEM and Jurkat cell lines, whereas Cimetidine fails to induce significant effects at similar concentrations. Diphenhydramine-induced apoptosis is evaluated in terms of morphology, flow cytometry, and the release of cytochrome c to the cytosol. Diphenhydramine inhibits cell proliferation without inducing apoptosis in human peripheral blood mononuclear cells. Diphenhydramine (500 nM) significantly reduces the baseline firing of the periaqueductal gray neurons without a significant effect on the frequency of postsynaptic potentials. Diphenhydramine at high concentration inhibits periaqueductal gray neurons, but at low concentrations it has no effect on the baseline-firing rate and it blocks the response to neurotensin and tomedial preoptic nucleus stimulation.

Brain Res. 2000 Oct 27;881(2):190-8; Oncol Res. 2004;14(7-8):363-72.