Remifentanil administration reveals biphasic phMRI temporal responses in rat consistent with dynamic receptor regulation.

ABSTRACT

Many pharmacological stimuli influence multiple neurotransmitter systems in the brain, and the dynamics of the functional brain response can vary regionally. In this study, the temporal response of cerebral blood volume (CBV) was employed to spatially segment cerebral effects due to infusion of a potent mu-opioid receptor agonist. Repeated intravenous injection of 10 mug/kg remifentanil in rats caused reproducible regional positive, negative, and biphasic changes in CBV. Three temporal processes were identified in the cerebral response and analyzed within the framework of the general linear model. Firstly, a slow component identified CBV changes that were almost exclusively negative, and the spatial distribution was similar to the inhibition produced by morphine (200 microg/kg). The largest CBV reductions occurred in caudate, accumbens, ventral hippocampus, cingulate, and piriform cortex. Secondly, a more rapid temporal component corresponded primarily with a regional distribution of positive changes in CBV consistent with GABAergic inhibition of hippocampal interneurons and associated projections. Thirdly, a response with the dynamics of mean arterial blood pressure correlated positively with CBV changes in hypothalamus, consistent with a central mechanism for control of blood pressure. We propose that the dominant source of the temporal variance in signal is dynamic modulation of drug targets by receptor endocytosis, an established effect in vitro. These results suggest that the temporal response of fMRI signal reflects underlying neurobiological processes, so that temporal decomposition strategies may aid interpretation of pharmacological mechanisms by identifying interconnected regions or those associated with common neural targets and processes.