Transcriptional and posttranslational plasticity and the generation of inflammatory pain

Inflammatory pain manifests as spontaneous pain and pain hypersensitivity. Spontaneous pain reflects direct activation of specific receptors on nocice ptor terminals by inflammatory mediators. Pain hypersensitivity is the cons equence of early posttranslational changes, both in the peripheral terminal s of the nociceptor and in dorsal horn neurons, as well as later transcript ion-dependent changes in effector genes, again in primary sensory and dorsa l horn neurons. This inflammatory neuroplasticity is the consequence of a c ombination of activity-dependent changes in the neurons and specific signal molecules initiating particular signal-transduction pathways. These pathwa ys phosphorylate membrane proteins, changing their function, and activate t ranscription factors, altering gene expression. Two distinct aspects of sen sory neuron function are changed as a result of these processes, basal sens itivity, or the capacity of peripheral stimuli to evoke pain, and stimulus- evoked hypersensitivity, the capacity of certain inputs to generate prolong ed alterations in the sensitivity of the system. Posttranslational changes largely alter basal sensitivity. Transcriptional changes bath potentiate th e system and alter neuronal phenotype, Potentiation occurs as a result of t he up-regulation in the dorsal root ganglion of centrally acting neuromodul ators and simultaneously in the dorsal horn of their receptors. This means that the response to subsequent inputs is augmented, particularly those tha t induce stimulus-induced hypersensitivity, Alterations in phenotype includ es the acquisition by A fibers of neurochemical features typical of C fiber s, enabling these fibers to induce stimulus-evoked hypersensitivity, someth ing only C fiber inputs normally can do. Elucidation of the molecular mecha nisms responsible provides new opportunities for therapeutic approaches to managing inflammatory pain.