In this paper, we have demonstrated that two peptides, SP and SRIF, which have been localized to and are released from small DRG neurons, have specific but different actions on mouse spinal cord neurons in PDC culture. SP has been shown to be excitatory by decreasing potassium conductance and to a lesser extent sodium conductance; SP also appeared to evoke release of neurotransmitter. SRIF has been shown to modify neurotransmitter release by a presynaptic action. The extensive experimental control that is possible over neurons in vitro permits precise measurements of specific membrane actions to be made and thus allows hypotheses of cellular mechanisms of peptide actions to be advanced. Predictions made based on these hypotheses should then be tested using intact preparations. A reasonable goal for such studies is a detailed understanding of the cellular and ionic mechanisms underlying actions in the CNS, PNS and gut.