Compartment-Specific Modulation of GABAergic Synaptic Transmission by μ-Opioid Receptor in the Mouse Striatum with Green Fluorescent Protein-Expressing Dopamine Islands

Abstract

The striatum is a heterogeneous mosaic of two neurochemically, developmentally, and functionally distinct compartments: the -opioid receptor (MOR)-enriched striosomes and the matrix. Preferential activation of the striosomes and persistent suppression of the matrix have recently been suggested to represent neural correlates of motor stereotypy. However, little is known concerning the physiological properties of the striosomes. We made patch-clamp recordings from medium spiny neurons in identified MOR-immunoreactive "dopamine islands" as striosomes in a slice preparation taken from transgenic mice expressing green fluorescent protein in tyrosine hydroxylase mRNA-containing neurons. Striosomal neurons differed electrophysiologically from cells in the matrix in having significantly less hyperpolarized resting membrane potentials and larger input resistances, suggesting developmental differences between the two types of cells. Moreover, corticostriatal EPSCs were inhibited by MOR activation to similar extents in the two compartments, although inhibition of IPSCs was observed only in the striosomes. This MOR-induced inhibition of IPSCs was presynaptically mediated, because MOR agonist invariably decreased IPSC amplitudes when postsynaptic G-protein was inactivated, significantly increased the paired-pulse ratio of the IPSCs, and decreased the frequency but not the amplitude of miniature IPSCs. These effects of MOR were mediated principally by 4-aminopyridine-sensitive K ϩ conductance via a cAMP-dependent pathway, which was further augmented by previous blockade of the protein kinase C cascade. These findings suggest that MOR activation by endogenous and/or exogenous MOR-selective opioid substances differentially regulates the activities of the striosome and matrix compartments and thus plays an important role in motivated behavior and learning.

Roles of μ-Opioid Receptors in GABAergic Synaptic Transmission in the Striosome and Matrix Compartments of the Striatum

“…In fact, presynaptic inhibition of corticostriatal excitatory inputs by MOR activation was demonstrated to be mediated by K + channel modulation in the rat striatum [30]. Likewise, we found that MOR activation inhibited GABA release mainly through activation of 4-AP-sensitive K + channels by suppression of the adenylate cyclase pathway in the striosomes [14]. On the other hand, involvement of the arachidonic acid cascade in the presynaptic modulation of IPSCs by MOR appeared unlikely in the striatum, although it has been reported in the periaqueductal gray and central amygdala [56,57].…”

“…3). This MORmediated suppression of GABAergic IPSCs in the strio- [14] somes was proved to be presynaptic. Negative presynaptic modulation of GABAergic inhibitory transmission takes place only in the striosome compartment.…”

“…Compared with the rapid progress in anatomical understanding of the striosome and matrix compartments, physiological studies have long been hampered by difficulty with selective identification of one compartment or the other due to the small size and patchy distribution of the striosomes. Recently, we found that brain slice preparations obtained from a transgenic mouse expressing green fluorescent protein (GFP) under the control of tyrosine hydroxylase (TH) gene promoter (TH-GFP mouse) were helpful in selective identification of each of the compartments and exhibited compartment-specific modulation of GABAergic synaptic transmission by MOR, which is selectively localized in the striosomes [14]. Then, how do the MOR in the striosomes influence the activity of the striatum?…”

Tramadol‐Induced Seizurogenic Effect: A Possible Role of Opioid‐Dependent γ‐Aminobutyric Acid Inhibitory Pathway

“…Furthermore, this inhibition of GABA receptors induced by tramadol has been shown to be secondary to its opioid receptor agonist activity. In addition, continued pharmacological opioid receptor agonist activity has been proven to precipitate seizures via a GABA inhibitory pathway [6,7]. Therefore, the present study has been designed to pharmacologically investigate the role of opioid and GABA receptors in the seizurogenic effect of tramadol on pentylenetetrazole-treated mice and on seizure-like behavioural symptomatology precipitated per se by tramadol.…”

Factors Related to Seizure in Tramadol Poisoning and Its Blood Concentration

“…Inhibition of GABA receptors has been found to potentiate the severity of seizures in animal models [13,14]. In addition, GABA receptor inhibition induced by tramadol can be secondary to its opioid receptor agonist activity [13], and continuing this agonist activity on opioid receptor has been proven to precipitate seizure due to inhibition of GABA pathways [15,16]. In addition to overdose, seizures have been reported in patients receiving tramadol at recommended doses [17].…”