Substance P was discovered in 1931 by von Euler and Gaddum. In the mid 1970'ies this peptide was found in small dorsal root ganglion neurons, suggesting involvement in pain. Subsequently several other neuropeptides have been found in DRG neurons, e.g. CGRP and somatostatin. After peripheral nerve injury, in models of neuropathic pain, there is a dramatic change in the phenotype of DRG neurons: substance P and CGRP are downregulated and several other peptides are upregulated, including VIP, galanin and NPY. This is considered a reaction to promote survival and regeneration as well as to combat pain. These results offer new ideas how to treat pain, for example using agonists at the galanin type 1 receptor (GalR1) and antagonists at GalR2. For transduction of signaling by galanin, and many other peptides, phospholipase C is an important enzyme. It is present in small DRG neurons, also in human DRGs, and systemic administration of a PLC inhibitor causes a long lasting increase in pain threshold in a neuropathic pain model, perhaps offering a novel approach to treatment of this type of serious pain.