Activation of μ- and δ-Opioid Receptors Causes Presynaptic Inhibition of Glutamatergic Excitation in Neocortical Neurons

Ostermeier, Andreas M.; Schlösser, B.; Schwender, Dirk; Sutor, Bernd

doi:10.1097/00000542-200010000-00029

Cited by 56 publications

(33 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The acute activation of opioid receptors results in decrease in neuronal excitability and neurotransmission by the activation of a class of inwardly rectifying potassium channels, and the inhibition of certain voltage-sensitive calcium channels (for review, see [15,16] ). In nociceptive transmission, for example, the activation of opioid receptors in the primary afferent C fi bers results in hyperpolarization of these neurons, decreased fi ring, inhibited release of excitatory neurotransmitters including glutamate [17] and substance P [18,19] from the central termini of these afferent fi bers in the dorsal horn of the spinal cord. Opioid receptors are also expressed in post-synaptic, intrinsic neurons within the spinal cord [20][21][22] .…”

Section: Homologous Desensitization and Down-regulationmentioning

confidence: 99%

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

et al. 2005

View full text Add to dashboard Cite

Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. ‘analgesic tolerance’. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.

show abstract

Section: Homologous Desensitization and Down-regulationmentioning

confidence: 99%

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Immunocytochemical studies revealed that DOR is localized at presynaptic terminals in a variety of neurons, including those of mammalian cortex (Bausch et al, 1995;Svingos et al, 1995). d-Opioid receptor activation has been shown to prevent the release of d-opioid receptor and extracellular K + D Chao et al glutamate from presynaptic vesicles, thereby reducing glutamate excitability (Tanaka and North, 1994;Ostermeier et al, 2000), which would decrease hyperexcitability-induced K + leakage through ionotropic glutamate receptors in neurons. It is very likely that DOR attenuation of anoxic K + derangement might involve multiple strategies involved in ionic homeostasis in the neurons although the precise mechanisms are not yet clear.…”

Section: L) (E-h)mentioning

confidence: 99%

Cortical δ-Opioid Receptors Potentiate K⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation

Chao

Donnelly

Yin

et al. 2006

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that d-opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K + , which plays a role in neuronal death, we asked whether DOR activation preserves K + homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K + -sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen-glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala 2 , D-Leu 5 ]-enkephalinamide attenuated the anoxia-and OGD-induced increase in extracellular K + and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K + and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K + homeostasis. These data suggest that activation of DOR protects the cortex against anoxia-or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K + homeostasis during anoxia or ischemia.

show abstract

“…It has been shown that activation of muopioid, and mainly DORs (e.g. DADLE receptors), depresses the glutamatergic excitatory transmission by presynaptic inhibition without evidence for a postsynaptic interaction between glutamate and opioid receptors [10,35] . This presynaptic mechanism presumably blocks the release of excitatory neurotransmitters.…”

Section: Discussionmentioning

confidence: 99%

“…The DOR receptor agonist DADLE has been shown to depress glutamatergic excitatory transmission in vitro [10] . The attenuation of the well-known deleterious effect of glutamate release [11] was suggested as one possible protective mechanism of opioid agonists [12] .…”

Section: Introductionmentioning

confidence: 99%

The Delta-Opioid Receptor Agonist D-Ala2-D-Leu2-Enkephalin Enhances Hypoxic Depression of Excitatory Synaptic Transmission and Improves Recovery of Rat Cortical Neurons from Hypoxia in vitro

Merkenschlager

Bloßfeld²,

Nieber³

2016

Pharmacology

View full text Add to dashboard Cite

We investigated the influence of the delta-opioid receptor-preferring agonist D-Ala2-D-Leu2-enkephalin (DADLE) in vitro during long- and short-term hypoxia on the single cortical neuron membrane currents, the postsynaptic currents (PSCs), and the postsynaptic potentials (PSPs) in rats. Rat cortical pyramidal neurons showed 2 distinct and prognostically relevant responses to hypoxia. Type A neurons that responded to hypoxia by an inward current, followed by a steady outward current, were shown to recover during subsequent reoxygenation. In contrast, type B neurons that responded by a steady inward current, indicative of gradual anoxic depolarisation, suffered irreversible membrane dysfunction and did not recover completely during reoxygenation. Pre-treatment with 1 µmol/l DADLE attenuated the hypoxic inward current and favored complete recovery of holding current and input resistance during reoxygenation, even when neurons were challenged by a second exposure to hypoxia. DADLE enhanced the inhibitory effect of hypoxia on PSPs and PSCs. We assume that this neuroprotective effect is transmitted by the additive effects of DADLE on the hypoxic PSP/PSC suppression, thereby inhibiting presynaptic glutamate release.

show abstract

Activation of μ- and δ-Opioid Receptors Causes Presynaptic Inhibition of Glutamatergic Excitation in Neocortical Neurons

Cited by 56 publications

References 1 publication

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

Cortical δ-Opioid Receptors Potentiate K⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation

The Delta-Opioid Receptor Agonist D-Ala2-D-Leu2-Enkephalin Enhances Hypoxic Depression of Excitatory Synaptic Transmission and Improves Recovery of Rat Cortical Neurons from Hypoxia in vitro

Contact Info

Product

Resources

About

Activation of μ- and δ-Opioid Receptors Causes Presynaptic Inhibition of Glutamatergic Excitation in Neocortical Neurons

Cited by 56 publications

References 1 publication

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

Is Paradoxical Pain Induced by Sustained Opioid Exposure an Underlying Mechanism of Opioid Antinociceptive Tolerance?

Cortical δ-Opioid Receptors Potentiate K+ Homeostasis During Anoxia and Oxygen–Glucose Deprivation

The Delta-Opioid Receptor Agonist D-Ala2-D-Leu2-Enkephalin Enhances Hypoxic Depression of Excitatory Synaptic Transmission and Improves Recovery of Rat Cortical Neurons from Hypoxia in vitro

Contact Info

Product

Resources

About

Cortical δ-Opioid Receptors Potentiate K⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation