Partial agonistic action of morphine in the rat vas deferens.

Ishii, Kunio; Yamamoto, Satoshi; Muraki, Takamura; Kato, Ryuichi

doi:10.1254/jjp.31.905

Cited by 4 publications

(4 citation statements)

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“…In fact, a drug that is a full agonist in one tissue may, due to lower R T or efficiency of coupling receptor activation to response, have lower potency in another tissue, or may be a partial agonist or even an antagonist in another (Figure ). For example, morphine is a full agonist for inhibition of adenylyl cyclase activity in HEK293 cells (Zaki et al ., ), yet is an extremely weak partial agonist/competitive antagonist in the rat vas deferens preparation (Ishii et al ., ; Smith and Rance, ). In some ways, the situation is not helped by pharmacological databases such as the IUPHAR database (http://www.iuphar-db.org/index.jsp), where morphine is defined as a full agonist at MOP receptors, but whether or not it behaves as a full or partial agonist depends totally upon the assay/tissue being used.…”

Section: Intrinsic Efficacymentioning

confidence: 97%

“…() described morphine as an agonist with relatively high intrinsic efficacy for Ca 2+ channel inhibition, which is a G protein‐mediated response, yet very low efficacy for internalization in these cells. On this basis, morphine could be classified as a G protein‐biased ligand, but this seems inconsistent with data from other systems, such as inhibition of the nerve‐evoked contractions in rat vas deferens (considered to be a G protein‐mediated response), where morphine is a very weak partial agonist/competitive antagonist compared to other MOP receptor agonists such as DAMGO (Ishii et al ., ; Smith and Rance, ). Furthermore, if morphine is a G protein‐biased agonist, it might be expected to display effects similar to those observed with recently identified G protein‐biased MOP receptor ligands (discussed below), such as reduced liability to induce tolerance and constipation (Lamb et al ., ; DeWire et al ., ), but this is certainly not the case.…”

Section: Morphine An Unbiased Ligand?mentioning

confidence: 97%

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Efficacy and ligand bias at the μ‐opioid receptor

Kelly

2013

British J Pharmacology

130

124

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In order to describe drug action at a GPCR, a full understanding of the pharmacological terms affinity, efficacy and potency is necessary. This is true whether comparing the ability of different agonists to produce a measurable response in a cell or tissue, or determining the relative ability of an agonist to activate a single receptor subtype and produce multiple responses. There is a great deal of interest in the μ-opioid receptor (MOP receptor) and the ligands that act at this GPCR not only because of the clinically important analgesic effects produced by MOP agonists but also because of their liability to induce adverse effects such as respiratory depression and dependence. Our understanding of the mechanisms underlying these effects, as well as the ability to develop new, more effective MOP receptor drugs, depends upon the accurate determination of the efficacy with which these ligands induce coupling of MOP receptors to downstream signalling events. In this review, which is written with the minimum of mathematical content, the basic meaning of terms including efficacy, intrinsic activity and intrinsic efficacy is discussed, along with their relevance to the field of MOP receptor pharmacology, and in particular in relation to biased agonism at this important GPCR. LINKED ARTICLESRecent reviews on aspects of efficacy can be found at:

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Section: Intrinsic Efficacymentioning

confidence: 97%

Section: Morphine An Unbiased Ligand?mentioning

confidence: 97%

Efficacy and ligand bias at the μ‐opioid receptor

Kelly

2013

British J Pharmacology

130

124

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“…In cultured cell models, the full agonist DAMGO was shown to cause GRK2/3‐mediated phosphorylation of MOR phosphorylation sites: S356, T357, T370, S375, T376, and T379 79–84 . This result was compared with the lower efficacy agonist morphine, which is typically considered a partial agonist in vitro although with systems‐dependent efficacy 44,85–88 . Morphine caused phosphorylation of S375 in MOR, produced minimal phosphorylation of T370, T376, and T379, and thus drove 5‐ to 15‐fold‐less multiphosphorylation of MOR 79–84 .…”

Section: Regulation Of Gpcr Signalingmentioning

confidence: 99%

A cellular perspective of bias at G protein‐coupled receptors

2020

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G protein-coupled receptors (GPCRs) modulate cell function over short-and long-term timescales. GPCR signaling depends on biochemical parameters that define the what, when, and where of receptor function: what proteins mediate and regulate receptor signaling, where within the cell these interactions occur,and how long these interactions persist. These parameters can vary significantly depending on the activating ligand. Collectivity, differential agonist activity at a GPCR is called bias or functional selectivity. Here we review agonist bias at GPCRs with a focus on ligands that show dramatically different cellular responses from their unbiased counterparts.

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“…The K, values of naloxone against dynorphin-(1-13) and a-neo-endorphin obtained in the present experiments (see Table 2) were close to that obtained in the guinea-pig ileum with K-receptor agonists. Furthermore, in the guinea-pig oesophagus, morphine acts as a partial agonist, as the drug does in the rat vas deferens (Huidobro, Huidobro-Toro & Miranda, 1980;Ishii, Yamamoto, Muraki & Kato, 1981).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterization of the opioid receptor in the submucous plexus of the guinea‐pig oesophagus

Kamikawa

Shimo

1983

British J Pharmacology

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1 The cholinergically mediated electrically-induced contractions of the submucous plexuslongitudinal muscularis mucosae preparation of the guinea-pig oesophagus were used to study the actions of opioid peptides and morphine. 2 The twitch contractions of the tissue (0.1 Hz, 0.5m s, supramaximal voltage) were inhibited by all the opioid peptides and morphine in a concentration-dependent manner. The order of potency was dynorphin-(1-13) > a-neo-endorphin > P-endorphin > [D-Ala2]-methionine-enkephalin >> aendorphin, methionine-enkephalin, leucine-enkephalin and morphine.3 The inhibitory actions of dynorphin-(1-13) (20 nM), cx-neo-endorphin (100 nM) and Pendorphin (3 jiM) were completely reversed either by naloxone (1 jiM) or by morphine (100 jiM). The Ke values of naloxone against dynorphin-(1-13) and a-neo-endorphin were 30 and 25 nm, respectively. 4 Increasing the concentration of calcium from 1.8 to 3.6 mM in Tyrode solution decreased the sensitivity of the tissue to dynorphin-(1-13) 7.4 times and to x-neo-endorphin 462 times. 5 The inhibitory actions of dynorphin-(1-13) (100nM) and ac-neo-endorphin (300nM) were inversely related to stimulus frequency, being most active at low frequencies (0.1-1 Hz), and least active at high (30 Hz). 6 Exogenously applied acetylcholine produced concentration-dependent contractions of the isolated muscularis mucosae, with an EC50 of 72.6±4.5nM. The contractile response of the oesophagus to acetylcholine was not affected by the pretreatment of the tissue with dynorphin-(1-13) (100 nM), a-neo-endorphin (300 nM) or P-endorphin (3 JiM).7 It is concluded that the submucous plexus-longitudinal muscularis mucosae of the guinea-pig oesophagus is inhibited by opioid peptides acting at prejunctional opioid receptors, probably of the K-subtype.

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Partial agonistic action of morphine in the rat vas deferens.

Abstract: Abstract-Effects of morphine on the force of contraction of rat vas deferens were investigated.Morphine and 8-endorphin decreased the electrically evoked twitch tension, in a dose dependent manner. The inhibitory effect of morphine, however, was much weaker than that of a-endorphin. These

Cited by 4 publications

References 12 publications

Efficacy and ligand bias at the μ‐opioid receptor

Efficacy and ligand bias at the μ‐opioid receptor

A cellular perspective of bias at G protein‐coupled receptors

Pharmacological characterization of the opioid receptor in the submucous plexus of the guinea‐pig oesophagus

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