An expanding knowledge of neuropeptides and their function has led to a profound change in our view of how the PAN contributes to pain. In addition to their expected direct action on postsynaptic cells in the dorsal horn, neuropeptides can modify transmitter release from nearby terminals of other PANs and/or diffuse to act on dorsal horn neurons at a considerable distance from their site of release (Fig. 2). Contrary to early expectations and despite the evidence that several neuropeptides excite central nociceptive neurons, there is no clear correspondence between neuropeptide content and physiologically defined classes of small-diameter primary afferents. There is, however, a tendency for populations of afferents innervating different organs to differ consistently in their peptide content. In fact, the peptide content of primary afferents is, in part, determined by specific factors in the tissues that they innervate. Furthermore, peptide content can change dramatically in response to certain prolonged stimuli or nerve damage. The lack of correspondence of peptide content and physiological response pattern, the plasticity of peptide content, its tissue specificity, and the possibility for action at a distance from the site of their release from central PAN terminals strongly suggest that PAN peptides have functions that are fundamentally different from those of the short-range actions of amino acid neurotransmitters that are also found in the PAN. Finally, nowhere is the plasticity of function of the PAN more evident than at its peripheral terminals. Long-term changes are produced in these terminals by a host of peptides that derive from a variety of cell types. The complexity of this transduction process is augmented by the activity- induced release of peripherally active neuropeptides from the PAN itself. In addition to the variety of fundamental neurobiological issues that recent studies of PANs have raised, they have also generated a great deal of clinical interest, in view of the role of the PAN in inflammation and its accessibility for study and for therapeutic intervention.