ABSTRACT
Delta opioid (DOP) receptors participate to the control of chronic pain and emotional responses. Recent data also identified their implication in spatial memory and drug-context associations pointing to a critical role of hippocampal delta receptors. To better appreciate the impact of repeated drug exposure on their modulatory activity, we used fluorescent knock-in mice that express a functional delta receptor fused at its carboxy-terminus with the green fluorescent protein in place of the native receptor. We then tested the impact of chronic morphine treatment on the density and distribution of delta receptor-expressing cells in the hippocampus. A decrease in delta receptor-positive cell density was observed in the CA1, CA3 and dentate gyrus without alteration of the distribution across the different GABAergic populations that mainly express delta receptors. This effect partly persisted after four weeks of morphine abstinence. In addition, we observed increased DOP receptor expression at the cell surface compared to saline-treated animals. In the hippocampus, chronic morphine administration thus induces DOP receptor cellular redistribution and durably decreases delta receptor-expressing cell density. Such modifications are likely to alter hippocampal physiology, and to contribute to long-term cognitive deficits.
Subject(s)
Hippocampus/drug effects , Morphine/pharmacology , Narcotics/pharmacology , Neurons/drug effects , Receptors, Opioid, delta/metabolism , Animals , Chronic Disease , Disease Models, Animal , Female , Gene Knock-In Techniques , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hippocampus/metabolism , Hippocampus/pathology , Immunohistochemistry , Male , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Transgenic , Morphine Dependence/metabolism , Morphine Dependence/pathology , Neurons/metabolism , Neurons/pathology , Receptors, Opioid, delta/geneticsABSTRACT
Compelling evidence indicates that the long (D2L) and the short (D2S) isoform of dopamine (DA) D2 receptors serve distinct physiological functions in vivo. To address the involvement of these isoforms in the control of synaptic transmission in the striatum, we measured the sensitivity to D2 receptor stimulation of glutamate- and GABA-mediated currents recorded from striatal neurons of three mutant mice, in which the expression of D2L and D2S receptors was either ablated or variably altered. Our data indicate that both isoforms participate in the presynaptic inhibition of GABA transmission in the striatum, while the D2-receptor-dependent modulation of glutamate release preferentially involves the D2S receptor. Accordingly, the inhibitory effects of the DA D2 receptor agonist quinpirole (10 microM) on GABA(A)-mediated spontaneous inhibitory postsynaptic currents (IPSCs)correlate with the total number of D2 receptor sites in the striatum, irrespective of the specific receptor isoform expressed. In contrast, glutamate-mediated spontaneous excitatory postsynaptic currents (EPSCs) were significantly inhibited by quinpirole only when the total number of D2 receptor sites, normally composed by both D2L and D2S receptors in a ratio favoring the D2L isoform, was modified to express only the D2S isoform at higher than normal levels. Understanding the physiological roles of DA D2 receptors in the striatum is essential for the treatment of several neuropsychiatric conditions, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and drug addiction.
Subject(s)
Corpus Striatum/metabolism , Glutamic Acid/metabolism , Receptors, Dopamine D2/metabolism , Synaptic Transmission/physiology , gamma-Aminobutyric Acid/metabolism , Animals , Corpus Striatum/drug effects , Dopamine Agonists/pharmacology , Evoked Potentials/drug effects , Evoked Potentials/physiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Male , Mice , Mice, Mutant Strains , Mutation , Neurons/drug effects , Neurons/metabolism , Organ Culture Techniques , Patch-Clamp Techniques , Quinpirole/pharmacology , Receptors, Dopamine D2/drug effects , Receptors, Dopamine D2/genetics , Synaptic Transmission/drug effectsABSTRACT
The treatment of chronic post-traumatic osteomyelitis with soft tissue damage requires debridement followed by plastic surgical soft tissue replacement. 47 patients were treated between the period of 1983 through to 1985 with a combination of extensive sequestrectomy followed by flap cover. In 15 cases a free muscle flap (M. latissimus dorsi) and in 32 cases a pedicled muscle flap (M. gastrocnemius, M. soleus) were employed. A successful outcome was achieved in 40 of the 47 patients.
Subject(s)
Fractures, Open/surgery , Osteomyelitis/surgery , Surgical Flaps , Tibial Fractures/surgery , Chronic Disease , Combined Modality Therapy , Humans , Postoperative Complications/surgery , Wound HealingABSTRACT
Delta opioid receptors participate to the control of chronic pain and emotional responses. Recent data also identified their implication in spatial memory and drug-context associations pointing to a critical role of hippocampal delta receptors. We examined the distribution of delta receptor-expressing cells in the hippocampus using fluorescent knock-in mice that express a functional delta receptor fused at its carboxyterminus with the green fluorescent protein in place of the native receptor. Colocalization with markers for different neuronal populations was performed by immunohistochemical detection. Fine mapping in the dorsal hippocampus confirmed that delta opioid receptors are mainly present in GABAergic neurons. Indeed, they are mostly expressed in parvalbumin-immunopositive neurons both in the Ammon's horn and dentate gyrus. These receptors, therefore, most likely participate in the dynamic regulation of hippocampal activity.