Research Paper
Subject Category: Neuropharmacology
British Journal of Pharmacology (2008) 153, 609–619; doi:10.1038/sj.bjp.0707598; published online 3 December 2007
Activities of mixed NOP and 
-opioid receptor ligands
B Spagnolo1, G Calo1, W E Polgar2, F Jiang2, C M Olsen2, I Berzetei-Gurske2, T V Khroyan3, S M Husbands4, J W Lewis4, L Toll2 and N T Zaveri2
- 1Section of Pharmacology, Department of Experimental and Clinical Medicine, National Institute of Neuroscience, University of Ferrara, Ferrara, Italy
- 2Biosciences Division, SRI International, Menlo Park, CA, USA
- 3Center for Health Sciences, SRI International, Menlo Park, CA, USA
- 4Department of Pharmacy and Pharmacology, University of Bath, Bath, UK
Correspondence: Dr L Toll, SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025, USA. E-mail: lawrence.toll@sri.com
Received 13 August 2007; Revised 28 September 2007; Accepted 30 October 2007; Published online 3 December 2007.
Abstract
Background and purpose:
Compounds that activate both NOP and 
-opioid receptors might be useful as analgesics and drug abuse medications. Studies were carried out to better understand the biological activity of such compounds.
Experimental approach:
Binding affinities were determined on membranes from cells transfected with NOP and opioid receptors. Functional activity was determined by [35S]GTP
S binding on cell membranes and using the mouse vas deferens preparation in vitro and the tail flick antinociception assay in vivo.
Key results:
Compounds ranged in affinity from SR14150, 20-fold selective for NOP receptors, to buprenorphine, 50-fold selective for -opioid receptors. In the [35S]GTPS assay, SR compounds ranged from full agonist to antagonist at NOP receptors and most were partial agonists at -opioid receptors. Buprenorphine was a low efficacy partial agonist at -opioid receptors, but did not stimulate [35S]GTPS binding through NOP. In the mouse vas deferens, each compound, except for SR16430, inhibited electrically induced contractions. In each case, except for N/OFQ itself, the inhibition was due to -opioid receptor activation, as determined by equivalent results in NOP receptor knockout tissues. SR14150 showed antinociceptive activity in the tail flick test, which was reversed by the opioid antagonist naloxone.
Conclusions and implications:
Compounds that bind to both -opioid and NOP receptors have antinociceptive activity but the relative contribution of each receptor is unclear. These experiments help characterize compounds that bind to both receptors, to better understand the mechanism behind their biological activities, and identify new pharmacological tools to characterize NOP and opioid receptors.
Keywords:
nociceptin, N/OFQ, opioid receptor, NOP, buprenorphine, mouse vas deferens, antinociception
Abbreviations:
CHO, Chinese hamster ovary; MC-CAM, methoclocinnamox; %MPE, percent maximal possible effect
