Multiple Targets of μ-Opioid Receptor-Mediated Presynaptic Inhibition at Primary Afferent Aδ- and C-Fibers

Heinke, Bernhard; Gingl, Ewald; Sandkühler, Jürgen

doi:10.1523/jneurosci.4060-10.2011

Cited by 133 publications

(115 citation statements)

References 61 publications

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“…We and others have shown previously that, in vitro, the MOR agonist DAMGO induces a powerful presynaptic depression at C-fiber terminals (Ikoma et al, 2007;Heinke et al, 2011). Similarly, in the present study, depression of C-fiberevoked field potentials by systemic remifentanil, fentanyl, and morphine required activation of spinal MORs and was associated with an increase in the PPR.…”

Section: Opioid-induced Depression At Spinal C-fiber Synapsessupporting

confidence: 86%

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Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

Heinl¹,

Drdla-Schutting²,

Xanthos³

et al. 2011

J. Neurosci.

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In addition to analgesia, opioids may also produce paradoxical pain amplification [opioid-induced hyperalgesia (OIH)] either on abrupt withdrawal or during continuous long-term application. Here, we assessed antinociceptive and pronociceptive effects of three clinically used opioids at C-fiber synapses in the rat spinal dorsal horn in vivo. During 60 min of intravenous infusions of remifentanil (450), C-fiber-evoked field potentials were depressed and pairedpulse ratios (PPR) were increased, indicating a presynaptic inhibition by all three opioids. After withdrawal, postsynaptic responses were enhanced substantially for the remaining of the recording periods of at least 3 h. Withdrawal from remifentanil led to long-term potentiation (LTP) of synaptic strength in C-fibers via activation of spinal -opioid receptors (MORs) and spinal NMDA receptors (NMDARs). Fentanyl and morphine caused an enhancement of synaptic transmission at C-fibers, which involved two distinct mechanisms: (1) an opioid withdrawal LTP that also required activation of spinal MORs and NMDARs and that was associated with a decrease in PPR suggestive of a presynaptic mechanism of its expression, and (2) an immediate-onset, descending facilitation of C-fiber-evoked field potentials during and after intravenous infusion of fentanyl and morphine. Immediate-onset, descending facilitation was mediated by the activation of extraspinal MORs, descending serotonergic pathways, and spinal 5-hydroxytryptamine-3 receptors (5-HT 3 Rs). Our study identified fundamentally different pronociceptive effects of clinically used opioids and suggests that OIH can be prevented by the combined use of NMDAR and 5-HT 3 R antagonists.

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Section: Opioid-induced Depression At Spinal C-fiber Synapsessupporting

confidence: 86%

“…Acute opioid application depresses transmitter release from central terminals of nociceptive fibers (Kohno et al, 1999;Heinke et al, 2011). This mechanism correlates to their analgesic effect.…”

Section: Introductionmentioning

confidence: 99%

Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

Heinl¹,

Drdla-Schutting²,

Xanthos³

et al. 2011

J. Neurosci.

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“…However, opioid receptors are one example in which the clinical action of a receptor agonist is linked closely to Ca V 2.2. The m-opioid receptor agonist morphine is a potent clinically used analgesic that interacts with m-opioid receptors (Mizoguchi et al, 2012), which then inhibits Ca V 2.2 channels in dorsal horn synapses (Heinke et al, 2011), along with concomitant activation of G protein-coupled inward rectifier potassium channels (Marker et al, 2005). The receptorinduced inhibition of Ca V 2.2 channels is thought to reduce presynaptic calcium levels, which in turn reduces synaptic transmission between these afferent nerve terminals (Kondo et al, 2005;Beaudry et al, 2011).…”

Section: Ca V 2 Channel Pathophysiologymentioning

confidence: 99%

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

865

992

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“…Presynaptic inhibition mediated by MORs occurs for other select types of primary afferents: nociceptive A␦ and C fiber projections to the spinal cord (see, e.g., Heinke et al 2011) as well as vagal visceral inputs to diverse neuron types in the cNST including GABAergic (Glatzer et al 2007;Glatzer and Smith 2005), A2 catecholaminergic (Cui et al 2012), and proopiomelanocortin (POMC) (Appleyard et al 2005) neurons. MOR-mediated presynaptic inhibition also occurs for intrinsic inhibitory and excitatory synaptic transmission in the cNST (Glatzer and Smith 2005).…”

Section: Damgo (Presynaptically) Suppresses St-evoked Responses In Thmentioning

confidence: 99%

The μ-opioid receptor agonist DAMGO presynaptically suppresses solitary tract-evoked input to neurons in the rostral solitary nucleus

Boxwell

Yanagawa

Travers

et al. 2013

Journal of Neurophysiology

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Boxwell AJ, Yanagawa Y, Travers SP, Travers JB. The -opioid receptor agonist DAMGO presynaptically suppresses solitary tract-evoked input to neurons in the rostral solitary nucleus. J Neurophysiol 109: 2815-2826, 2013. First published March 13, 2013 doi:10.1152/jn.00711.2012.-Taste processing in the rostral nucleus of the solitary tract (rNST) is subject to modulatory influences including opioid peptides. Behavioral pharmacological studies suggest an influence of -opioid receptors in rNST, but the underlying mechanism is unknown. To determine the cellular site of action, we tested the effects of the -opioid receptor agonist DAMGO in vitro. Whole cell patch-clamp recordings were made in brain stem slices from GAD67-GFP knockin mice expressing enhanced green fluorescent protein (EGFP) under the control of the endogenous promoter for GAD67, a synthetic enzyme for GABA. Neuron counts showed that ϳ36% of rNST neurons express GABA. We recorded monosynaptic solitary tract (ST)-evoked currents (jitter Յ 300 s) in both GAD67-EGFP-positive (GAD67ϩ) and GAD67-EGFP-negative (GAD67Ϫ) neurons with equal frequency (25/31; 22/28), but the inputs to the GAD67ϩ neurons had significantly smaller paired-pulse ratios compared with GAD67Ϫ neurons. DAMGO (0.3 M) significantly suppressed ST-evoked currents in both cell types (mean suppression ϭ 46 Ϯ 3.3% SE), significantly increased the paired-pulse ratio of these currents, and reduced the frequency of spontaneous miniature excitatory postsynaptic currents but did not diminish their amplitude, indicating a presynaptic site of action. Under inhibitory amino acid receptor blockade, DAMGO was significantly more suppressive in GAD67ϩ neurons (59% reduction) compared with GAD67Ϫ neurons (35% reduction), while the reverse was true in normal artificial cerebrospinal fluid (GAD67ϩ: 35% reduction; GAD67Ϫ: 57% reduction). These findings suggest that DAMGO suppresses activity in rNST neurons predominantly via a presynaptic mechanism, and that this effect may interact significantly with tonic or evoked inhibitory activity.

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Multiple Targets of μ-Opioid Receptor-Mediated Presynaptic Inhibition at Primary Afferent Aδ- and C-Fibers

Cited by 133 publications

References 61 publications

Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

Distinct Mechanisms Underlying Pronociceptive Effects of Opioids

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

The μ-opioid receptor agonist DAMGO presynaptically suppresses solitary tract-evoked input to neurons in the rostral solitary nucleus

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