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Comparative Study
, 6, 3

Pharmacological Profiles of Opioid Ligands at Kappa Opioid Receptors

Comparative Study

Pharmacological Profiles of Opioid Ligands at Kappa Opioid Receptors

Parham Gharagozlou et al. BMC Pharmacol.


Background: The aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a human embryonic kidney cell system stably expressing only the mouse kappa-opioid receptors. Receptor activation was assessed by measuring the inhibition of cyclic adenosine mono phosphate (cAMP) production stimulated by 5 microM forskolin. Intrinsic activities and potencies of these ligands were determined relative to the endogenous ligand dynorphin and the kappa agonist with the highest intrinsic activity that was identified in this study, fentanyl.

Results: Among the ligands studied naltrexone, WIN 44,441 and dezocine, were classified as antagonists, while the remaining ligands were agonists. Intrinsic activity of agonists was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The absolute levels of inhibition of cAMP production by each ligand was used to describe the rank order of intrinsic activity of the agonists; fentanyl = lofentanil > or = hydromorphone = morphine = nalorphine > or = etorphine > or = xorphanol > or = metazocine > or = SKF 10047 = cyclazocine > or = butorphanol > nalbuphine. The rank order of affinity of these ligands was; cyclazocine > naltrexone > or = SKF 10047 > or = xorphanol > or = WIN 44,441 > nalorphine > butorphanol > nalbuphine > or = lofentanil > dezocine > or = metazocine > or = morphine > hydromorphone > fentanyl.

Conclusion: These results elucidate the relative activities of a set of opioid ligands at kappa-opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of these opioid ligands at this receptor.


Figure 1
Figure 1
Dose response curves of inhibition of adenylyl cyclase activity by representative ligands in HEK-κ cells. Varying concentration of 2 full agonists (lofentanil and fentanyl) and one partial agonist (nalbuphine) were used to determine the potency and intrinsic activity of each ligand in inhibiting the effect of 5 μM forskolin in producing cAMP, as described under methods. The 100% on the y-axis corresponds to the cAMP levels in the absence of any drug, i.e.: forskolin alone, for all figures. Data presented are the average from 2 or more experiments carried out in duplicate. Error bars represent standard error of the mean (SEM) of the normalized data. Data have been normalized and SEM calculated as described under methods. (A) Full agonist lofentanil, (B) Full agonist, fentanyl, (C) Partial agonist, nalbuphine.
Figure 2
Figure 2
Antagonism of inhibition of adenylyl cyclase activity by a representative ligand in HEK-κ cells. Reversal of the inhibitory effect of etorphine by the antagonist Win 44,441 is shown. Maximal cAMP levels were in the range of 400–1000 pmole/well. Data presented are the average from 2 or more experiments carried out in duplicate. Error bars represent standard error of the mean.

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