Dissertation Abstract

Anatomical Analysis of MU and Delta Opioid Receptor Systems in the Brain and Changes in the Actions of Opioids Within the Dentate Gyrus Associated With Temporal Lobe Epilepsy

Anti-peptide antibodies were used to localize mu and delta opioid receptors and GIRK1 ion channels throughout the rat and mouse brain, respectively. Delta opioid receptor immunoreactivity was found in axons and nerve terminals throughout the brain and correlated well, though not completely with autoradiographic distribution. Double-labeled tissue showed localization of delta opioid receptors on GABAergic terminals in the hippocampus. Mu opioid receptor immunoreactivity was detected in brain regions that were previously found to contain mu opioid binding sites using autoradiography. The distribution of GIRK1 immunoreactivity in the brain correlated well with a previous in situ hybridization study. Double-labeled tissue revealed colocalization of GIRK1 and mu opioid receptor immunoreactivities in somata of subpopulations of neurons in many but not all regions of the rat brain.

The pilocarpine model of temporal lobe epilepsy was used to study time-dependent changes in dentate gyrus circuitry following seizures. Seizures decreased mu and delta opioid receptor immunoreactivities in the granule cell layer and hilus, and hilus respectively. Increased mu and delta opioid receptor and GABA immunoreactivities were seen in the inner molecular layer. Physiological changes in circuitry were investigated using the in vitro hippocampal slice preparation. The disinhibitory effects of DAMGO and bicuculline were greatly depressed 5-13 days after pilocarpine injection but returned to control levels within 6 weeks. Both the amplitude and the effects of DAMGO on monosynaptic evoked IPSCs were slightly decreased 5-13 days following pilocarpine, but significantly increased at 6 weeks. DAMGO significantly decreased the amplitude of spontaneous IPSCs at 6 weeks following pilocarpine injection, but not in controls. The delta opioid receptor agonist, DPDPE, principally inhibited excitatory transmission in saline treated animals without affecting either spontaneous or evoked IPSCs. DPDPE-induced inhibition of excitability became more pronounced at 6 weeks following pilocarpine injection. This study showed a seizure-induced loss of neurons expressing the mu and delta opioid receptor protein. Transient, partial losses of opioid receptor and GABA mediated effects were followed by longer-term increases which returned physiological measures to control or even increased levels.

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