Loss of Corticostriatal Mu-Opioid Receptors in α-Synuclein Transgenic Mouse Brains

Ultrastructural, neurochemical, and molecular alterations within the striatum are associated with the onset and progression of Parkinson’s disease (PD). In PD, the dopamine-containing neurons in the substantia nigra pars compacta (SNc) degenerate and reduce dopamine-containing innervations to the striatum. The loss of striatal dopamine is associated with enhanced corticostriatal glutamatergic plasticity at the early stages of PD. However, with disease progression, the glutamatergic corticostriatal white matter tracts (WMTs) also degenerate. We analyzed the levels of Mu opioid receptors (MORs) in the corticostriatal WMTs, as a function of α-Synuclein (α-Syn) toxicity in transgenic mouse brains. Our data show an age-dependent loss of MOR expression levels in the striatum and specifically, within the caudal striatal WMTs in α-Syn tg mouse brains. The loss of MOR expression is associated with degeneration of the myelinated axons that are localized within the corticostriatal WMTs. In brains affected with late stages of PD, we detect evidence confirming the degeneration of myelinated axons within the corticostriatal WMTs. We conclude that loss of corticostriatal MOR expression is associated with degeneration of corticostriatal WMT in α-Syn tg mice, modeling PD.

Effects of GABAA Receptors in Dorsal Hippocampus on Memory Retention of Cholestatic Rats

The molecular mechanisms that result in cognitive deficits following cholestasis are mainly unknown. As there are many GABAA receptors in the hippocampus CA1 region and the crucial role for GABA in modulating memory, we evaluated the effects of GABAA receptor agents in the CA1 of cholestatic rats on memory retention. The interaction between GABAergic and opioidergic systems in the CA1 on memory was also investigated. The effects of administration of GABAA receptor agonist and antagonist, muscimol (60, 120 and 240 ng/ side) and bicuculline (100, 200 and 400 ng/ side), into CA1 on memory retention were studies using passive avoidance learning (PAL) task in bile duct ligated (BDL) rats. Naloxone (250 ng/ side), the mu-opioid receptor antagonist, was also co-administered alone or with bicuculline (400 ng/ side) to indicate the interaction between opioidergic and GABAergic system. Cholestasis inhibited memory retrieval is shown by the decrease in the step-through latency (STLr). Administration of muscimol or bicuculline alone after training potentiated or attenuated respectively amnesia in BDL rats dose-dependently. Naloxone (250 ng /side) alone increased STLr in BDL-treated rats. Bicuculline (100 ng/side) alone antagonized the amnesic effect of muscimol (120 ng/side). Co-administration of bicuculline and naloxone or muscimol and naloxone caused a significant difference in STLr compared to only naloxone treated rats which show the interaction between two systems on memory retention in cholestssis. Bicuculline (100 ng/side) microinjection alone antagonized the amnesic effect of muscimol (120 ng/side). We indicated the contribution of intra-CA1 GABAA receptors on memory retention in cholestatic rats by the PAL test. Blockade of each GABAA or mu-opioid receptors alone could attenuate the amnesia in BDL rats. Furthermore, blockade of both GABAA or mu-opioid receptors reversed the memory deficit in BDL-treated rats, which shows the interaction between GABAergic and opioidergic systems on memory retention in this test.

A caged DAMGO for selective photoactivation of endogenous mu opioid receptors

Photoactivatable drugs and peptides are valuable tools that can drive quantitative studies into endogenous receptor signaling in relatively intact tissue preparations with high spatiotemporal resolution. We previously developed photoactivatable or caged variants of the opioid neuropeptides [Leu5]-enkephalin and dynorphin A (1-8), but these reagents activate multiple opioid receptors simultaneously upon photolysis. To achieve selective engagement of mu opioid receptors (MORs), we developed a photoactivatable derivative of the MOR-selective peptide agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). Starting from commercially available DAMGO, we appended a negatively charged carboxynitroveratryl (CNV) caging group to the N-terminal tyrosine side chain (Y) to produce CNV-Y-DAMGO. Dose-response curves in a heterologous functional assay revealed that CNV-Y-DAMGO is ~1,000-fold less potent than DAMGO at MORs. In acute hippocampal brain slices, CNV-Y-DAMGO photoactivation with ultraviolet light resulted in rapid, transient suppression of inhibitory synaptic transmission, and this was blocked by the MOR-selective antagonist CTAP. These results validate CNV-Y-DAMGO as a photopharmacological reagent for manipulating endogenous MOR signaling in brain tissue with light.

Himalayan Ficus palmata L. Fruit Extract Showed In Vivo Central and Peripheral Analgesic Activity Involving COX-2 and Mu Opioid Receptors

Analgesic drugs like morphine and non-steroidal anti-inflammatory drugs exhibit several harmful effects. Here, we show for the first time the analgesic activity of Ficus palmata L. fruit extract (FPFE) on different analgesic rat models along with the in silico studies of some of the main phytochemicals of this plant. We performed in vivo pain models, along with in silico docking studies against the active site of COX-2 protein and mu-opioid receptors. A significant (p < 0.05) analgesic effect of FPFE was observed, and it was found that rutin has good pose and score as compared to diclofenac and morphinan antagonist (X-ligand), and psoralen has binding affinity almost equal to diclofenac, but a lower binding affinity as compared to rutin. The results proved that F. palmata fruits have the potential to ameliorate painful conditions.

Mu opioid receptors acutely regulate adenosine signaling in a thalamo-striatal circuit.

Endogenous adenosine plays a crucial role in maintaining energy homeostasis and adenosine levels are tightly regulated across neural circuits. In the dorsal medial striatum (DMS) adenosine inhibits neurotransmitter release, but the source and mechanism underlying its accumulation are largely unknown. Opioids also inhibit neurotransmitter release in the DMS and influences adenosine accumulation after prolonged exposure. However, how these two neurotransmitter systems interact acutely is also largely unknown. This study demonstrates that activation of mu opioid receptors (MORs), but not delta opioid receptors (DORs) or kappa opioid receptors (KORs), inhibits tonic activation of adenosine A1Rs via a cyclic adenosine monophosphate (cAMP) dependent mechanism in both male and female mice. Further, selectively knocking-out MORs from presynaptic terminals and postsynaptic medium spiny neurons (MSNs) revealed that activation of MORs on D1R positive MSNs, but not D2R positive MSNs, is necessary to inhibit tonic adenosine signaling on presynaptic terminals. Given the role of D1R positive MSNs in movement and motivated behaviors, these findings reveal a novel mechanism by which these neurons regulate their own synaptic inputs.