Second messengers, the substantia gelatinosa and injury-induced persistent pain.

Although there is now unequivocal evidence that the circuitry within the substantia gelatinosa is a major contributor to the transmission and control of nociceptive messages, this was not known 35 years ago, when Pat Wall first focussed attention on this region. In addition to being the target of neurochemically distinct nociceptors, this region contains a heterogeneous population of excitatory and inhibitory interneurons. This review focuses on the contribution of second messenger systems that are found in the substantia gelatinosa. In particular the review highlights their critical contribution to the development of persistent pain conditions in the setting of tissue and nerve injury. Several of the studies used animals with deletions of genes that encode major second messenger molecules, including protein kinase A, C and nitric oxide synthase. Our laboratory has shown that mice with a deletion of the gene that encodes the gamma isoform of protein kinase C (which is almost exclusively expressed in a population of interneurons of the inner part of the substantia gelatinosa) have completely normal acute pain responses. However, the allodynia that characteristically develops after injury does not occur in these mice, particularly when it is generated by partial sciatic nerve injury. By contrast, deletion of genes that encode protein kinase A subunits only show deficits in the development of tissue inflammation-induced pain. These differences highlight the selectivity that characterizes the contribution of different second messenger molecules. Because of the restricted distribution of these molecules, it is likely that they are activated by different populations of primary afferent nociceptor and under very different conditions of injury. Understanding the circuitry within the substantia gelatinosa is thus critical to elucidating the mechanisms through which these second messenger molecules contribute to the development of persistent pain in the setting of injury.