Inability of an opioid antagonist lacking negative intrinsic activity to induce opioid receptor up‐regulation <i>in vivo</i>

Morris, Brian J.; Millan, Mark J.

doi:10.1111/j.1476-5381.1991.tb12271.x

Cited by 12 publications

(4 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…histamine H 2 receptors, β 2 -adrenoceptors, α 2 -adrenoceptors etc., whereas neutral antagonists do not (for review see Milligan and Bond 1997). Prolonged treatment of animals in vivo with the opioid inverse agonist naloxone up-regulates opioid receptors whereas the neutral antagonist MR2266 has no effect (Morris and Millan 1991). Most dopamine D 2 receptor antagonists with antipsychotic action up-regulate D 2 receptor density upon prolonged exposure and are inverse agonists (Wilson et al 2001).…”

Section: Discussionmentioning

confidence: 98%

Failure to detect in vivo inverse agonism of the 5-HT 1B receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs

Stenfors

Ross

2002

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

The possibility that 5-HT(1B) receptors display constitutive activity in vivo, i.e. have a basal agonist-independent activity, was examined in guinea-pigs depleted of endogenous brain 5-HT by pre-treatment with reserpine. Under these conditions (5 mg/kg s.c. reserpine 24 h before the experiment), hypothalamic 5-HT concentration was reduced by more than 97%. In reserpine-treated animals, 5-HT synthesis [measured as the accumulation of 5-hydroxytryptophan (5-HTP) after inhibition of the aromatic amino acid decarboxylase with m-hydroxybenzylhydrazine dihydrochloride (NSD 1015, 100 mg/kg s.c.)] was similar to that in non-treated guinea-pigs. The formation of 5-hydroxyindoleacetic acid (5-HIAA) was enhanced by reserpine treatment. The 5-HT(1B/1D) receptor agonist 3-( N-methylpyrrolidin-2- R-ylmethyl)-5-(3-nitropyrid-2-ylamino)-1 H-indole (CP-135,807) decreased 5-HT synthesis and 5-HIAA formation to the same extent in reserpine-treated and naive animals showing that the terminal 5-HT(1B) autoreceptors were functionally active during reserpine treatment. The 5-HT(1B) inverse agonist 1'-methyl-5-([2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl)-4-yl]carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] hydrochloride (SB-224289, 4 mg/kg s.c.), which in naive guinea-pigs significantly enhanced 5-HIAA formation and tended to enhance 5-HT synthesis, had no effect in the reserpine-treated animals. Likewise, SB-224289 did not change the rectal temperature in reserpine-treated guinea-pigs although the agonist CP-135,807 had a significant hypothermic effect in these animals. It is concluded that no constitutive activity of 5-HT(1B) autoreceptors (5-HIAA formation) or 5-HT(1B) heteroreceptors (rectal temperature) could be detected under the in vivo experimental conditions used.

show abstract

Section: Discussionmentioning

confidence: 98%

Failure to detect in vivo inverse agonism of the 5-HT 1B receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs

Stenfors

Ross

2002

Naunyn-Schmiedeberg's Archives of Pharmacology

View full text Add to dashboard Cite

show abstract

“…Thus, these antagonists can be considered as possessing negative agonist activity at 6 opiate receptors. The essential difference between 'pure' antagonists and those possessing 'negative agonist' properties was underlined in studies by Millan et al (1988) and Morris & Millan (1991), who showed that unlike naloxone long-term exposure to MR 2266 failed to up-regulate central I, 6 or K opiate binding sites or to produce supersensitivity to opiate agonists.…”

Section: Functional Dissociation Of Tolerance and Dependencementioning

confidence: 99%

Evidence for functional dissociation of dependence and tolerance in guinea‐pig isolated ileal segments following 20 hour exposure to morphine in vitro

Coynel

Davis

Mason

et al. 1993

British J Pharmacology

View full text Add to dashboard Cite

1 In the present study we have examined the relationship between tolerance and dependence in isolated ileal segments from the guinea-pig under three different conditions: fresh preparations not previously exposed to morphine (fresh/morphine naive); preparations stored overnight at 4°C in modified KrebsHenseleit saline (overnight-stored/morphine-naive); preparations stored overnight at 4°C in KrebsHenseleit saline containing 10 J.M morphine and extensively washed with modified Krebs-Henseleit saline to remove residual morphine (overnight-stored/morphine-exposed). 2 Morphine produced a concentration-dependent inhibition of the response of ileal segment to 0.1 Hz, 1 ms and 10 V transmural field stimulation in fresh/morphine-naive, overnight-stored/morphine-naive and overnight-stored/morphine-exposed preparations. The maximum effect observed was similar in all three preparations -approximately 80% inhibition. Although, morphine was significantly more potent in the fresh/morphine-naive preparations (pD2 6.72 ± 0.05, n = 8) than either the overnight-stored/ morphine-naive (pD2 6.42 ± 0.11, n = 8) or the overnight-stored/morphine-exposed (pD2 6.44 ± 0.14, n = 8), there was no significant difference between the overnight models in their sensitivity to morphine.The latter observation indicates that overnight exposure to ileal segments to 1O lM morphine at 4°C failed to induce tolerance to morphine.3 The 1t opiate receptor antagonist, naloxone (10 giM), produced contractions in both fresh/morphinenaive and overnight-stored/morphine-naive ileal segments following acute exposure to 10 fLM morphine. Naloxone (10 gM) also produced contractions in 2/9 fresh/morphine-naive, 1/9 overnight-stored/morphine-naive and 7/9 overnight-stored/morphine-exposed preparations in the absence of morphine. The greater incidence of naloxone-induced contractions in overnight-stored/morphine-exposed preparations, suggests that dependence in this model is the product of adaptive changes that outlive the presence of morphine. 4 The selective x2-adrenoceptor agonists, clonidine (0.3 j.M) and 5-bromo-6-[2-imidazolin-2-ylamino]-quinoxaline bitartrate (UK-14304, 1 p4M), inhibited naloxone-induced contractions in overnight-stored/ morphine-exposed preparations of ileal segments (n = 4 preparations for each agonist), suggesting that the response is due to transmitter release from the myenteric plexus. 5 The findings in the present study indicate that tolerance and dependence to morphine in ileal segments of the guinea-pig can be functionally dissociated by overnight exposure to morphine at 4°C. The development of tolerance to morphine, unlike dependence, appears to be a temperature-dependent process. This also raises the possibility that naloxone possesses intrinsic negative agonism at morphinesensitive receptors, which is manifested as a functional response only after adaptive changes in the myenteric plexus following exposure to morphine.

show abstract

“…As observed with opioid agonists, treatment with antagonists also affects the MOR-µ-MOR-µ* equilibrium. Generally, treatment with inverse agonists tends to sensitize MOR and enhance the active state (MOR-µ*) while neutral antagonists favor the MOR-µ ground state [45]. In addition, naloxone turns from a weak inverse agonist at DOR into a partial agonist at DOR upon pretreatment with an inverse agonist of DOR [46].…”

Section: Neutral Antagonists and Inverse Agonistsmentioning

confidence: 99%

Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to μ Opioid Receptors in Analgesia and Addiction

Sadée

McKew²

2022

Molecules

View full text Add to dashboard Cite

Numerous G-protein-coupled receptors (GPCRs) display ligand-free basal signaling with potential physiological functions, a target in drug development. As an example, the μ opioid receptor (MOR) signals in ligand-free form (MOR-μ*), influencing opioid responses. In addition, agonists bind to MOR but can dissociate upon MOR activation, with ligand-free MOR-μ* carrying out signaling. Opioid pain therapy is effective but incurs adverse effects (ADRs) and risk of opioid use disorder (OUD). Sustained opioid agonist exposure increases persistent basal MOR-μ* activity, which could be a driving force for OUD and ADRs. Antagonists competitively prevent resting MOR (MOR-μ) activation to MOR-μ*, while common antagonists, such as naloxone and naltrexone, also bind to and block ligand-free MOR-μ*, acting as potent inverse agonists. A neutral antagonist, 6β-naltrexol (6BN), binds to but does not block MOR-μ*, preventing MOR-μ activation only competitively with reduced potency. We hypothesize that 6BN gradually accelerates MOR-μ* reversal to resting-state MOR-μ. Thus, 6BN potently prevents opioid dependence in rodents, at doses well below those blocking antinociception or causing withdrawal. Acting as a ‘retrograde addiction modulator’, 6BN could represent a novel class of therapeutics for OUD. Further studies need to address regulation of MOR-μ* and, more broadly, the physiological and pharmacological significance of ligand-free signaling in GPCRs.

show abstract

Inability of an opioid antagonist lacking negative intrinsic activity to induce opioid receptor up‐regulation in vivo

Cited by 12 publications

References 21 publications

Failure to detect in vivo inverse agonism of the 5-HT 1B receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs

Failure to detect in vivo inverse agonism of the 5-HT 1B receptor antagonist SB-224289 in 5-HT-depleted guinea-pigs

Evidence for functional dissociation of dependence and tolerance in guinea‐pig isolated ileal segments following 20 hour exposure to morphine in vitro

Ligand-Free Signaling of G-Protein-Coupled Receptors: Relevance to μ Opioid Receptors in Analgesia and Addiction

Contact Info

Product

Resources

About