The nervous and immune systems may communicate through the action of neurotransmitters on mast cells. We used patchclamp electrophysiology to assess the responses of rat peritoneal mast cells (PMC) to low levels of substance P (SP), which are likely to occur in situ. SP at 50 nM, or even 10,000 times reduced to 5 pM, triggered an outwardly rectified Cl- current (50 nM: 10 of 10 cells; 5 pM: 10 of 11 cells), although degranulation never occurred. Electrical responses were delayed (mean 102.6 s for 5 pM SP), appearing as brief current pulses. Reapplication of SP resulted in peak current augmentation (mean 15.3 pA before exposure to SP, 47.3 pA after 1st exposure, and 116.0 pA after 2nd exposure to 5 pM SP). Cells repetitively exposed to SP degranulated 5-15 min and > 25 min after the second exposure to 50 nM SP (10 of 10 cells) or 5 pM SP (5 of 9 cells), respectively. This effect was reduced by 10 microM 5-nitro-2-(3-phenylpropylamino)benzoic acid or when extracellular Ca2+ was removed, indicating a dependence on Cl- conductance and extracellular Ca2+. We propose that whole cell current oscillations in the absence of degranulation are the functional correlate of priming, a process that increases cellular responsiveness for the subsequent stimulation.