The fundamental unit of pain is the cell

The molecular/genetic era has seen the discovery of a staggering number of molecules implicated in pain mechanisms [18,35,61,69,96,133,150,202,224]. This has stimulated pharmaceutical and biotechnology companies to invest billions of dollars to develop drugs that enhance or inhibit the function of many these molecules. Unfortunately this effort has provided a remarkably small return on this investment. Inevitably, transformative progress in this field will require a better understanding of the functional links among the ever-growing ranks of "pain molecules," as well as their links with an even larger number of molecules with which they interact. Importantly, all of these molecules exist side-by-side, within a functional unit, the cell, and its adjacent matrix of extracellular molecules. To paraphrase a recent editorial in Science magazine [223], although we live in the Golden age of Genetics, the fundamental unit of biology is still arguably the cell, and the cell is the critical structural and functional setting in which the function of pain-related molecules must be understood. This review summarizes our current understanding of the nociceptor as a cell-biological unit that responds to a variety of extracellular inputs with a complex and highly organized interaction of signaling molecules. We also discuss the insights that this approach is providing into peripheral mechanisms of chronic pain and sex dependence in pain.