Evidence for lack of modulation of μ‐opioid agonist action by δ‐opioid agonists in the mouse vas deferens and guinea‐pig ileum

Elliott, J.M.; Traynor, John R.

doi:10.1111/j.1476-5381.1995.tb13314.x

Cited by 12 publications

(6 citation statements)

References 28 publications

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“…48 and present study), consistent with functional expression by myenteric neurons. These observations derived from the mouse colon are in accordance with data from the human (3,14,34,44) and rat (28,30) intestine but differ from the guinea pig intestine, where DADLE has minimal effect on neurogenic contractions (22,61).…”

Section: Dor Inhibits Colonic Motility Through a Peripheral Mechanismsupporting

confidence: 87%

Inflammation-associated changes in DOR expression and function in the mouse colon

DiCello

Saito

Rajasekhar

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Endogenous opioids activate opioid receptors (ORs) in the enteric nervous system to control intestinal motility and secretion. The μ-OR mediates the deleterious side effects of opioid analgesics, including constipation, respiratory depression, and addiction. Although the δ-OR (DOR) is a promising target for analgesia, the function and regulation of DOR in the colon are poorly understood. This study provides evidence that endogenous opioids activate DOR in myenteric neurons that may regulate colonic motility. The DOR agonists DADLE, deltorphin II, and SNC80 inhibited electrically evoked contractions and induced neurogenic contractions in the mouse colon. Electrical, chemical, and mechanical stimulation of the colon evoked the release of endogenous opioids, which stimulated endocytosis of DOR in the soma and proximal neurites of myenteric neurons of transgenic mice expressing DOR fused to enhanced green fluorescent protein. In contrast, DOR was not internalized in nerve fibers within the circular muscle. Administration of dextran sulfate sodium induced acute colitis, which was accompanied by DOR endocytosis and an increased density of DOR-positive nerve fibers within the circular muscle. The potency with which SNC80 inhibited neurogenic contractions was significantly enhanced in the inflamed colon. This study demonstrates that DOR-expressing neurons in the mouse colon can be activated by exogenous and endogenous opioids. Activated DOR traffics to endosomes and inhibits neurogenic motility of the colon. DOR signaling is enhanced during intestinal inflammation. This study demonstrates functional expression of DOR by myenteric neurons and supports the therapeutic targeting of DOR in the enteric nervous system. NEW & NOTEWORTHY DOR is activated during physiologically relevant reflex stimulation. Agonist-evoked DOR endocytosis is spatially and temporally regulated. A significant proportion of DOR is internalized in myenteric neurons during inflammation. The relative proportion of all myenteric neurons that expressed DOR and the overlap with the nNOS-positive population are increased in inflammation. DOR-specific innervation of the circular muscle is increased in inflammation, and this is consistent with enhanced responsiveness to the DOR agonist SNC80.

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Section: Dor Inhibits Colonic Motility Through a Peripheral Mechanismsupporting

confidence: 87%

Inflammation-associated changes in DOR expression and function in the mouse colon

DiCello

Saito

Rajasekhar

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The δ antagonist activity of 5a was also determined in MVD versus DPDPE. 23 When 5a was preincubated for 30 min with the tissue, a K e of 14.5 nM was obtained, showing very much lower potency than expected from the δ antagonist potency in the [ 35 S]GTPγS assay. However, with increased incubation time (2 h), 5a caused a much bigger shift in the concentration effect curve for DPDPE such that the IC 50 obtained was significantly different when 3 nM 5a was incubated for 2 h compared to 30 nM 5a for 30 min.…”

Section: Resultsmentioning

confidence: 91%

4‘-Arylpyrrolomorphinans: Effect of a Pyrrolo-N-benzyl Substituent in Enhancing δ-Opioid Antagonist Activity

et al. 2001

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A new method for the preparation of N-benzylpyrrolomorphinans has been developed. Thus Michael reaction of the benzylimines of oxycodones and oxymorphones with nitrostyrenes gave a series of 4'-aryl-N-benzylpyrrolomorphinans. These were selective delta antagonists of much higher in vitro potency (with 5a having K(e) delta = <1 nM) than their binding affinities predicted. In mice in vivo assays 5a showed good delta antagonist activity in the anti-writhing analgesic assay and also inhibited delta agonist-induced convulsant activity.

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“…It is therefore possible that the requirement of MOR for some DOR effects may be region-or neuron-specific. In support to this hypothesis, MOR/DOR interactions were shown to occur in some brain regions but not in peripheral tissues (Franklin andTraynor, 1991, Elliott andTraynor, 1995). Whether or not these interactions may differ within various laminae of the same spinal cord segment and that they play a crucial role in DOR-mediated analgesia in the CFA model of inflammation will need further investigations.…”

Section: Discussionmentioning

confidence: 92%

Essential role of mu opioid receptor in the regulation of delta opioid receptor–mediated antihyperalgesia

2007

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Analgesic effects of delta opioid receptor (DOR)-selective agonists are enhanced during persistent inflammation and arthritis. Although the underlying mechanisms are still unknown, membrane density of DOR was shown to be increased 72 h after induction of inflammation, an effect abolished in mu opioid receptor (MOR)-knockout (KO) mice (Morinville et al., 2004b). In this study, we demonstrated a crucial role of MOR in DOR-mediated antihyperalgesia. Intrathecal administration of the DOR selective agonist deltorphin II failed to induce antihyperalgesic effects in MOR-KO mice, whereas it dose-dependently reversed thermal hyperalgesia in wildtype mice. The antihyperalgesic effects of deltorphin II were blocked by naltrindole but not CTOP suggesting that this agonist was mainly acting through DOR. SNC80-induced antihyperalgesic effects in MOR-KO mice were also attenuated as compared to littermate controls. In contrast, kappa opioid receptor knockout did not affect deltorphin II-induced antihyperalgesia. As evaluated using mice lacking endogenous opioid peptides, the regulation of DOR's effects was also independent of β-endorphin, enkephalins, or dynorphin opioids known to be released during persistent inflammation. We therefore conclude that DOR-mediated antihyperalgesia is dependent on MOR expression but that activation of MOR by endogenous opioids is probably not required.

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Evidence for lack of modulation of μ‐opioid agonist action by δ‐opioid agonists in the mouse vas deferens and guinea‐pig ileum

Abstract: 1 There is evidence from in vivo studies for an interaction of .t-and b-opioid ligands. In the present work this concept has been investigated using the mouse vas deferens and guinea-pig ileum myenteric plexus-longitudinal preparations.

Cited by 12 publications

References 28 publications

Inflammation-associated changes in DOR expression and function in the mouse colon

Inflammation-associated changes in DOR expression and function in the mouse colon

4‘-Arylpyrrolomorphinans: Effect of a Pyrrolo-N-benzyl Substituent in Enhancing δ-Opioid Antagonist Activity

Essential role of mu opioid receptor in the regulation of delta opioid receptor–mediated antihyperalgesia

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