In vivo opiate receptor binding of oripavines to μ, σ and κ sites in rat brain as determined by an ex vivo labeling method

doi:10.1016/0014-2999(85)90379-6

European Journal of Pharmacology

Volume 114, Issue 3, 27 August 1985, Pages 343-353

https://doi.org/10.1016/0014-2999(85)90379-6 Get rights and content

Abstract

The relative in vivo receptor affinities of three oripavine drugs given subcutaneously were determined at the μ, σ and κ type of opiate binding sites in rat brain. The oripavines include the agonist etorphine, the antagonist diprenorphine and the mixed agonist-antagonist buprenophine. With the use of μ, δ and κ specific labeling conditions in brain homogenates immediately after sacrifice (ex vivo labeling), the method relies on the assay of those receptor sites that remain unbound in vivo. Because of the slow receptor binding kinetics of the oripavines, little or no dissociation of the in vivo ligand occurs during the ex vivo labeling period. All three drugs displayed lower affinity in vivo at the δ sites relative to μ sites, whereas the κ affinites were highly variable. Etorphine displayed considerable μ selectivity, while burpenorphine's affinity at the μ and κ sites was similar. The apparent in vivo binding affinities obtained from the ex vivo labeling approach are compatible with previous results where tracers were applied in vivo. The dramatic differences of the in vivo and in vitro opiate receptor binding properties of the oripavines demonstrate the need for in vivo receptor binding parameters in the analysis of the function of individual receptor types.

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We are not aware of any pharmacokinetic study of morphine in zebrafish, but Lau and colleagues (Lau et al., 2006) have shown that adult zebrafish display behavioural changes and measurable morphine levels in the brain after administration via the water. Since buprenorphine is a partial agonist of the μ, δ and κ opioid receptors (Reisine and Bell, 1993; Richards and Sadée, 2003), we expect the full agonist morphine to have stronger effects. Although the effects of buprenorphine may be mild, they are specific since we have been able to prevent the antinociceptive effect by occupying the opioid receptors with naloxone, a high affinity antagonist of the μ opioid receptor.
The underlying processes of nociception and pain are, despite the rodent models available, still not fully understood. One of the drawbacks of rodent model systems is the difficulty to screen compound libraries for their influence on nociception, thus slowing down the discovery of novel analgesics for clinical use.
Rodent behavioural tasks have been previously adapted for larval zebrafish in our group and in the current manuscript we investigated the possibilities of zebrafish larvae as an additional model system to study nociception and pain and their underlying mechanisms.
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Overall, the body of literature suggests that buprenorphine is an opioid with unique and complex pharmacology, i.e., it can act as an agonist and/or antagonist at different classes of opioid receptors (Lutfy and Cowan, 2004). Although buprenorphine has been shown to interact in vivo and in vitro with multiple opioid receptors, its primary activity is as a partial agonist at the mu-opioid receptor and antagonist at the kappa receptor (Leander et al., 1988; Martin et al., 1976; Richards and Sadee, 1985). The majority of data shows that buprenorphine acts as a delta opioid receptor antagonist and as a partial agonist at the opioid receptor-like 1 (ORL1) receptor (Marquez et al., 2008).
Although morphine is often the best option for treating acute and chronic severe pain, its analgesic activity can be blocked in situations in which there are elevated levels of chemokines. Indeed, recently we have shown that elevated brain levels of the chemokine stromal cell-derived growth factor-1alpha (SDF-1α/CXCL12, the ligand of the HIV co-receptor CXCR4) diminish the antinociceptive effect of morphine. The purpose of the present study was to investigate whether such an effect is restricted to morphine or extends to other opioid medications such as buprenorphine. A sterilized stainless-steel C313G guide cannula was implanted into the periaqueductal grey (PAG), a brain region critical to the processing of pain signals, and a primary site of action of many analgesic compounds. The cold-water (−3 °C) tail-flick test (CWT) was used to measure antinociception. Rats were pretreated with SDF-1α/CXCL12 administered into the PAG, and the antinociceptive actions of buprenorphine were measured. Direct infusion of SDF-1α/CXCL12 into the PAG failed to alter the antinociceptive action of buprenorphine. The presence of SDF-1α/CXCL12 in the PAG differentially alters the antinociceptive function of opioid medications. While it was able to diminish the antinociception induced by morphine (Adler et al., 2006), SDF-1α/CXCL12 did not affect the buprenorphine-induced antinociception. Buprenorphine appears to be more effective in the presence of high levels of SDF-1α/CXCL12 in the brain (which frequently occurs during neuroinflammatory conditions).
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Together, the present results suggest that the ability of buprenorphine to interact with the ORL1 receptor compromises its acute motor stimulatory and rewarding actions. Buprenorphine, an opioid with mixed agonist/antagonist activity, has a high affinity for the mu opioid receptor (Sadee et al., 1982; Richards and Sadee, 1985; Negus et al., 1989, 2002; Huang et al., 2001; Lutfy et al., 2003). Previous studies have shown that buprenorphine also interacts with the ORL1 receptor (Wnendt et al., 1999; Hawkinson et al., 2000; Bloms-Funke et al., 2000; Huang et al., 2001; Lutfy et al., 2003; Hou et al., 2004; Yamamoto et al., 2006; Ciccocioppo et al., 2007).
We have previously shown that the ability of buprenorphine to activate the opioid receptor-like (ORL1) receptor compromises its antinociceptive effect. Furthermore, morphine has been shown to alter the level of orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the ORL1 receptor, raising the possibility that the endogenous OFQ/N/ORL1 receptor system may be involved in the actions of these opioids. Thus, using mice lacking the ORL1 receptor and their wild-type littermates, the present study assessed the role of the ORL1 receptor in psychomotor stimulant and rewarding actions of buprenorphine and morphine. Morphine (5, 10 mg/kg) dose-dependently increased motor activity and induced conditioned place preference. However, the magnitude of each response was comparable for the mutant mice and their wild-type littermates. In contrast, buprenorphine (1 mg/kg) induced greater motor stimulation in ORL1 receptor knockout mice as compared with their wild-type littermates. Further, single conditioning with buprenorphine (3 mg/kg) induced place preference in mutant mice but not in their wild-type littermates. The results of binding assay showed that buprenorphine concentration-dependently (0–1000 nM) displaced specific binding of [³H]-OFQ/N in brain membrane of wild-type mice. Together, the present results suggest that the ability of buprenorphine to interact with the ORL1 receptor modulates its acute motor stimulatory and rewarding effects.
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Available ligands are tabulated in Table 1. Diprenorphine (DPN) binds with similar, approximately 1 nmol/L, affinities at all three major opioid receptor subtypes [58] and does not have a reference region because binding in all putative reference regions can be blocked with naloxone [59]. It is a partial agonist at δ and κ receptors and an antagonist at the μ receptor [60].
Many breakthrough scientific discoveries have been made using opioid imaging. Developments include the application of ever higher resolution whole-brain positron emission tomography (PET) scanners, the availability of several radioligands, the combination of PET with advanced structural imaging, advances in modeling macroparameters of PET ligand binding, and large-scale statistical analysis of imaging datasets. Suitable single-photon emission computed tomography (SPECT) tracers are lacking, but with the increase in the number of available PET (or PET/CT) cameras and cyclotrons thanks to the clinical successes of PET in oncology, PET may become widespread enough to overcome this. In the coming decade, there should be a more widespread application of the available techniques to patients and an impact in clinical medicine.
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Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of μ opioid receptors (μORs). This study examined the duration of action of BUP at μORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers.
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In vivo opiate receptor binding of oripavines to μ, σ and κ sites in rat brain as determined by an ex vivo labeling method

Abstract

J. Biol. Chem.

Naunyn-Schmiedeb. Arch. Pharmacol.

J. Pharmacol. Exp. Ther.

Mol. Pharmacol.

J. Biol. Chem.

European J. Pharmacol.

J. Pharmacol. Exp. Ther.

Prog. Neuro-Psychopharmacol. Biol. Psychiat.

Neuropharmacology

Interactions of narcotic antagonists and antagonists-analgesics

J. Pharm. Pharmacol.

Coupling opiate receptors to adenylate cyclase: requirement for Na+ and GTP

Novel opiate binding sites selective for benzomorphan drugs

Morphiceptin (NH4-Tyr-Pro-Phe-Pro-CONH2): a potent and specific agonist for morphine (μ) receptors

Science

Interaction of enkephalin with opiate receptors in intact cultured cells

Mol. Pharmacol.

In vivo receptor binding of the opiate partial agonist, buprenorphine, correlated with its agonistic and antagonistic actions

Br. J. Pharmacol.

Coupling opiate receptors to adenylate cyclase: requirement for Na⁺ and GTP

Morphiceptin (NH₄-Tyr-Pro-Phe-Pro-CONH₂): a potent and specific agonist for morphine (μ) receptors