Delta Opioid Receptors Presynaptically Regulate Cutaneous Mechanosensory Neuron Input to the Spinal Cord Dorsal Horn

Bardoni, Rita; Tawfik, Vivianne L.; Wang, Dong; François, Amaury; Solórzano, Carlos Ortiz de; Shuster, S. Andrew; Choudhury, Papiya; Betelli, Chiara; Cassidy, Colleen E.; Smith, Kristen; Nooij, Joriene C. de; Mennicken, Françoise; O’Donnell, Dajan; Kieffer, Brigitte L.; Woodbury, C. Jeffery; Basbaum, Allan I.; MacDermott, Amy B.; Scherrer, Grégory

doi:10.1016/j.neuron.2014.03.006

Cited by 56 publications

(104 citation statements)

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“…Peptidergic C-fibers are essential to acute heat pain as well as injury-induced heat hyperalgesia (Cavanaugh et al, 2009) and have been shown to project to laminae I and II outer of the spinal cord ) where robust NOP Receptor Biology and Function immunoreactivity of NOP-eGFP is also observed. A smaller proportion of small unmyelinated (NF200-) NOP-eGFP+ DRG neurons bind IB4, indicating that NOP receptors are also present in the non-peptidergic DRG neurons, which are involved in mechanical pain Cavanaugh et al, 2009;Scherrer et al, 2009;Vrontou et al, 2013;Bardoni et al, 2014). These studies suggest that NOP receptors might regulate the function of two classes of C nociceptors that respond to both heat and mechanical pain.…”

Section: B Location Of Nociceptin Opioid Peptide Receptorsmentioning

confidence: 89%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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Section: B Location Of Nociceptin Opioid Peptide Receptorsmentioning

confidence: 89%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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“…Previous attempts at targeting ␦R to manage pain have mainly focused on developing better ␦R agonists (Scherrer et al, 2009;Gavériaux-Ruff and Kieffer, 2011;Bardoni et al, 2014). However, these efforts have largely been unsuccessful, as available agonists show poor in vivo efficacy, necessitating the use of high doses that cause adverse effects.…”

Section: Discussionmentioning

confidence: 99%

“…␦R expressed in nociceptive neurons can reduce cAMP and inhibit Ca 2ϩ channels to inhibit neuronal activity (Jutkiewicz et al, 2006;Cahill et al, 2007;Pradhan et al, 2011;Bardoni et al, 2014). ␦R agonists can cause antinociception in some conditions, and they show reduced abuse liability compared with current opioids that target the opioid receptor (R) ( Vanderah, 2010;Gendron et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A PTEN-Regulated Checkpoint Controls Surface Delivery of δ Opioid Receptors

et al. 2017

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The ␦ opioid receptor (␦R) is a promising alternate target for pain management because ␦R agonists show decreased abuse potential compared with current opioid analgesics that target the opioid receptor. A critical limitation in developing ␦R as an analgesic target, however, is that ␦R agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of ␦R in sensory neurons contributes to this low ␦R agonist efficacy in vivo by limiting surface ␦R expression. Using direct visualization of ␦R trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains ␦R in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases ␦R from this checkpoint and stimulates delivery of exogenous and endogenous ␦R to the neuronal surface both in vitro and in vivo. PTEN inhibition in vivo increases the percentage of TG neurons expressing ␦R on the surface and allows efficient ␦R-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the ␦R, explain the low efficacy of ␦R agonists in vivo, and provide evidence that active ␦R relocation is a viable strategy to increase ␦R antinociception.

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“…showed that DOR presynaptically regulate mechanical inputs from sensory neurons to spinal cord (74). Thus, it is conceivable that DORs expressed on mechanosensitive fibers mediate the pain-suppressive effects of enkephalins released from the RVMpre neurons, even when RVM release of GABA is blocked.…”

Section: Discussionmentioning

confidence: 99%