Changes in gene expression underlie short-term to long-term adaptation processes within the CNS in response to changes in nuclear calcium concentration. We have characterized the DREAM protein, the first known calcium sensor with intrinsic transcriptional repressor activity that is directly regulated by changes in the concentration of Ca²⁺ ions (Nature 398:80-84, 1999). Expression of DREAM mRNA and protein has been observed widely distributed in the CNS and the spinal cord. To understand the role of DREAM in neuronal function in vivo, we have analyzed the responses to noxious stimulation in wild-type mice and compared to transgenic mice over expressing dominant negative mutants of DREAM in neurons by the use of the neuron-specific CaMKIIa promoter. Expression of the dominant negative mutant in spinal cord and various supraspinal nuclei related to pain transmission and endogenous pain control pathways in transgenic mice is correlated with an increased sensitivity to different forms of noxious stimulation. Importantly, transgenic mice showed a decreased expression of prodynorphin as well as a reduction in kappa opioid receptor mRNA levels in spinal cord. Thus, a significant de-regulation in the expression of two genes central for pain transmission-control mechanisms is part of the transcriptional network regulated by Ca²⁺ and DREAM in spinal and supraspinal neurons. Gene profile analysis of transgenic spinal cord showed, however, additional changes in gene expression that may as well determine the hyperalgesic phenotype observed in DREAM transgenic mice.