Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor

doi:10.1016/S0196-9781(00)00252-7

Peptides

Volume 21, Issue 7, July 2000, Pages 1141-1146

https://doi.org/10.1016/S0196-9781(00)00252-7 Get rights and content

Abstract

The nociceptin/orphanin FQ (N/OFQ) receptor (e.g. the human ortholog ORL1) has been shown to be pharmacologically distinct from classic opioid receptors. Recently, we have identified buprenorphine as a full ORL1 agonist using a reporter gene assay. For further functional analysis, buprenorphine’s effects on ORL1 receptors were investigated using a K⁺ channel (GIRK1) assay in Xenopus oocytes and GTPγS assay in CHO-K1 membrane preparations. In both assays, buprenorphine behaved as a partial agonist compared to nociceptin itself. The N/OFQ agonism of buprenorphine might contribute to actions of buprenorphine in pain models in vivo beside its μ- or κ-opioid receptor mediated effects.

Introduction

Buprenorphine (Temgesic®, F. Hoffman La Roche, Grenzach, Germany; Reckitt & Colman, Hull, UK) is a synthetic opiate that is clinically used for treatment of moderate-to-severe pain [10], [13], [23], [28], [41], [44]. Compared to other opiates, buprenorphine is outstanding in its long duration of action and the relatively low addiction potential [15]. In animal models, buprenorphine displays a biphasic or even triphasic dose response curve with a first peak around 0.5 mg/kg subcutaneous (s.c.), followed by a decline up to doses of 10 mg/kg s.c. and a second increasing arm in even higher doses [8], [29], [30], [40]. Underlying mechanisms of the complex pharmacology of buprenorphine are controversially discussed in the literature including partial agonism at μ and antagonism or agonism at κ-opioid receptors, respectively [5], [17], [20], [29], [34], [40]. Interestingly, we have detected strong agonistic activities of buprenorphine at the nociceptin/orphanin FQ (N/OFQ) receptor (e.g. the human ortholog ORL1) using a reporter gene assay [46]. The heptadecapeptide nociceptin was discovered as the endogenous ligand of the ORL1 receptor showing both hyperalgesic and antinociceptive properties in vivo [7], [12], [24], [31], [33], [38], [45], [47]. On the cellular level, nociceptin inhibits cAMP formation and opens potassium channels by coupling to G_i/o-proteins and inhibits calcium channels [4], [18], [24], [27], [31], [42]. In the present study, the activities of buprenorphine at ORL1 receptors were further investigated using two different heterologous expression systems: 1) Xenopus oocytes taking advantage of functional coupling of ORL1 receptors to G-protein activated inwardly rectifying K⁺ (GIRK1) channels [14], [22], and 2) CHO-K1 cell membranes using agonist-stimulated [³⁵S]GTPγS incorporation [36], [37]. The data obtained here and in the reporter gene assay are discussed with respect to the role of buprenorphine’s ORL1 component in pain modulation beside its opioid mechanisms.

Section snippets

Expression in Xenopus oocytes and electrophysiological investigations

A pBluescriptIIKS vector containing the GIRK1 cDNA (kindly provided by Prof. Dr W. Schreibmayer) was linearized with XhoI and the cRNA was synthesized using T7 promotor with the respective RNA polymerase and a 5′cap (mMessage Machine Kit, Ambion). A pZeoSV2+ vector containing the human ORL1 receptor cDNA [46] was linearized with BamHI and the cRNA was synthesized using T3 promotor with the respective RNA polymerase as described above. After incubation and DNase-treatment according to the

Results

Buprenorphine induced inward currents up to 750 nA when applied to oocytes co-expressing ORL1 with GIRK1. A typical original recording is shown in Fig. 1 A. After administration of buprenorphine (1 μmol/l), membrane currents reached a peak within 2 min and desensitized down to 49.2 ± 6.1% of peak value 16 min after beginning of buprenorphine application. After a 2 min application, buprenorphine induced currents returned to baseline within 2 to 4 min, which contrasts to buprenorphine’s

Discussion

Recently, we have identified the opioid buprenorphine as a full agonist at the ORL1 receptor using a reporter gene assay [46]. In the present study, we used a G-protein activated K⁺ channel (GIRK1) assay in Xenopus oocytes and a GTPγS assay in CHO-K1 membrane preparations. In both approaches, buprenorphine induced significant agonism with potencies of 0.166 and 0.079 μmol/l, respectively. The data presented here essentially confirm our result in the reporter gene assay. Buprenorphine, however,

Acknowledgements

We thank Prof. Dr W. Schreibmayer (Institut for Medical Physics and Biophysics, University of Graz, Austria) for gifts of GIRK1-cDNA containing plasmid and Dipl.-Ing. Markus Valdor, Ira Haben, Susanna Biermann, and Dieter Hildebrandt for excellent technical assistance.

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^☆: The present study was funded by the Bundesministerium für Bildung und Forschung (BMBF; Federal Ministry of Education and Research; Grant number: 01GG9818/0).

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Regular paperAgonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor☆

Abstract

Introduction

Section snippets

Expression in Xenopus oocytes and electrophysiological investigations

Results

Discussion

Acknowledgements

Neurosci Lett

The significance of receptor binding. Br J Anaesth

Trends Neurosci

Mol Brain Res

Neuropharmacology

J Neurosci Methods

Br J Anaesth

Neuroscience

Neurosci Lett

FEBS Lett

Brain Res

Brain Res

Antinociceptive actions of morphine and buprenorphine given intrathecally in the conscious rat

Br J Pharmacol

The effect of nociceptin on Ca2+ channel current and intracellular Ca2+ in the SH-SY5Y human neuroblastoma cell line

Br J Pharmacol

Agonist and antagonist properties of buprenorphine, a new antinociceptive agent

Br J Pharmacol

The animal pharmacology of buprenorphine, an oripavine analgesic agent

Br J Pharmacol

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

Br J Pharmacol

Oogenesis in Xenopus laevis (Daudin). IStages of oocyte development in laboratory maintained animals

J Morphol

Postoperative pain relief with high-dose epidural buprenorphinea double-blind study

Acta Anaesthsiol Scand

Blocking effects of barium and hydrogen ions on the potassium current during anamalous rectification in the starfish egg

J Physiol

Characterization of nociceptin hyperalgesia and allodynia in conscious mice

Br J Pharmacol

Randomized trial comparing buprenorphine and diamorphine for chest pain in suspected myocardial infarction

Br Med J

Human pharmacology and abuse potential of the analgesic buprenorphine

Arch Gen Psychiat

Regular paper
Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor☆

The effect of nociceptin on Ca²⁺ channel current and intracellular Ca²⁺ in the SH-SY5Y human neuroblastoma cell line