Mu opioid receptors occur throughout the brain, but central sites where ligand neuromodulatory effects occur during glucopenia have not been identified. The present studies investigated whether septal, preoptic, and hypothalamic neurons that express immunoreactivity for this receptor are transcriptionally activated in response to the glucose antimetabolite, 2-deoxy-D-glucose (2DG), and if intracerebroventricular (icv) administration of the selective mu receptor antagonist, CTOP, modifies this functional response to glucose substrate imbalance. Neurons labeled for mu receptor-immunoreactivity (-ir) were observed in the lateral septal nucleus (LS), medial septum (MS), anterior division of the stria terminalis (BSTa), median preoptic nucleus (MEPO), medial preoptic nucleus (MPN), parastrial nucleus (PS), anterior hypothalamic periventricular nucleus (PVa), and lateral hypothalamic area (LPO). 2DG injection (400 mg/kg i.p.) resulted in co-labeling of mu receptor-positive neurons in the LS, MS, BSTa, MEPO, PVa, and LPO for nuclear Fos-ir. Icv delivery of CTOP decreased mean numbers of co-labeled neurons in the LS, MS, BSTa, and MEPO. These results provide evidence for transactivational effects of glucopenia on mu opioid receptor-expressing neurons within the septum, preoptic area, and hypothalamus, and suggest that the functional status of these receptors within discrete septopreoptic sites may be critical for maximal glucoprivic induction of the Fos stimulus-transcription cascade within local cells. These results thus support the view that the neural loci described above may serve as substrates for regulatory effects of mu opioid receptor ligands on central compensatory activities during acute glucose deprivation.