The immunosuppressant FK506 activates capsaicin- and bradykinin-sensitive DRG neurons and cutaneous C-fibers

Immunosuppressant drug FK506, which is widely used for the treatment of atopic dermatitis, has multiple actions on the nervous system. In order to elucidate the mechanisms underlying transient burning sensation elicited by topical application of FK506 to the skin of atopic patients, we investigated if FK506 directly activates sensory neurons and fibers, or not. Ca(2+) imaging study on cultured DRG neurons of rats revealed that application of FK506 raised intracellular Ca(2+) levels in a subpopulation of small DRG neurons (3.1% of DRG neurons responsive to high K(+) solution). When DRGs from inflamed rats were used, the incidence increased to 7.4%. FK506 sensitive neurons also responded to a subsequent application of capsaicin (89.5% in normal, and 100% in inflamed rats) and bradykinin (31.6% in normal, and 80.9% in inflamed rats). Single fiber recordings in the skin-nerve preparation confirmed the results of cell culture study, showing that application of FK506 enhanced neuronal discharges of single C-fibers that are responsive to heat and bradykinin. These findings, taken together, indicate that FK506 application on inflamed skin may activate nociceptive C-fibers, which bear bradykinin receptors and capsaicin-sensitive heat transducer of TRP family, TRPV1.