Modulation of opioid gene expression is preceded by the transcription of the AP-1 transcription factors in the brain. The AP-1 transcription complex is composed of two families of proteins: c-fos and fos-related antigens (fra) and the 3 jun proteins. These proteins form heterodimers which recognize and bind to the AP-1 DNA element in the promotor area of the genes. Through this mechanism, gene transcription is modulated. Both the prodynorphin (pDYN) and the proenkephalin (pENK) genes contain AP-1 elements in their promotor regions, suggesting that these factors regulate these genes. We have been examining whether these transcription factors regulate these peptide genes in the rat brain and adrenal gland. Acute administration of the seizure-inducing drug, kainate, induces AP-1 protein expression and modulates the expression of both pDYN and pENK genes in the rat hippocampus. Using anticonvulsants to block kainate-activated neuronal activity, AP-1 protein expression and DNA binding are both inhibited as well as the increase in opioid gene expression, demonstrating the expression of both opioid gene expresssion and AP-1 proteins are correlated with neuronal activity. During development, rat pups at any age ae susceptible to seizure activity after kainate; however, neither the AP-1 proteins nor the opioid genes are induced in the hippocampus until postnatal day 14. Of interest, the postnatal day 7 hippocampus contains a high basal level of AP-1 DNA binding, which seems to be due to the development of glial cells. Therefore, there is a development-dependent regulation of the expression of AP-1 proteins and opioid genes in the hippocampus after seizure activity. Kainate treatment also causes neuronal death in the hippocampus which leads to reactive gliosis. During reactive gliosis, glial cells increase expression of many peptides including proenkephalin. We have found an increased level of AP-1 DNA binding in areas of reactive gliosis, suggesting AP-1 transcription factors may be modulating gene expression in reactive glia.
