Pharmacological profiles of opioid ligands at Kappa opioid receptors

Abstract

BackgroundThe 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 κ-opioid receptors. Receptor activation was assessed by measuring the inhibition of cyclic adenosine mono phosphate (cAMP) production stimulated by 5 μM forskolin. Intrinsic activities and potencies of these ligands were determined relative to the endogenous ligand dynorphin and the κ agonist with the highest intrinsic activity that was identified in this study, fentanyl.ResultsAmong 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 ≥ hydromorphone = morphine = nalorphine ≥ etorphine ≥ xorphanol ≥ metazocine ≥ SKF 10047 = cyclazocine ≥ butorphanol > nalbuphine. The rank order of affinity of these ligands was; cyclazocine > naltrexone ≥ SKF 10047 ≥ xorphanol ≥ WIN 44,441 > nalorphine > butorphanol > nalbuphine ≥ lofentanil > dezocine ≥ metazocine ≥ morphine > hydromorphone > fentanyl.ConclusionThese results elucidate the relative activities of a set of opioid ligands at κ-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.

Novel Molecular Targets of Dezocine and Their Clinical Implications

“…(1) In fact, a recent study suggested that dezocine is a kappa antagonist. (3) We confirmed this finding by demonstrating the compound’s inability to activate the receptor and its capacity to antagonize the agonist effects of salvinorin A, a potent and highly selective kappa receptor agonist, and nalbuphine, a non-selective kappa receptor agonist. Further study is needed to demonstrate whether this kappa receptor antagonism is connected to the compound’s lack of addictive properties.…”

“…Though initially identified as a kappa receptor agonist, a later study suggests that dezocine is a kappa receptor antagonist. (3) Further study is needed to resolve this discrepancy. Since dezocine is a partial mu antagonist, in theory, a concerted use of dezocine together with a mu receptor agonist like morphine should decrease the analgesia effect of morphine significantly.…”

Role of central and peripheral opiate receptors in the effects of fentanyl on analgesia, ventilation and arterial blood-gas chemistry in conscious rats

“…The mechanisms responsible for the analgesic and ventilatory depressant effects of fentanyl and analogs have been extensively investigated (Dahan et al, 1998; Sarton et al, 1999; Stein et al, 2009). Although fentanyl is thought of as a selective µ-OR agonist (Trescot et al, 2008; Hajiha et al, 2009) and has high affinity for µ-ORs (Raynor et al, 1994; Huang et al, 2001), it also activates δ- and κ-ORs with affinities/intrinsic activities of biological significance (Yeadon and Kitchen, 1990; Zhu et al, 1996, Butelman et al, 2002; Gharagozlou et al, 2006). For example, whereas fentanyl has low affinity for κ-ORs it has a remarkably high efficacy at these ORs (Gharagozlou et al, 2006).…”

Adverse Drug Reactions in the ICU

“…Analgesic-induced delirium could occur by interaction with other medications, opioids with serotonergic properties, and/or kappa-opioid agonism [309]. Fentanyl and/or methadone may interact with linezolid or other monoamine oxidase inhibitors (MAOI) or serotonergic medication resulting in serotonin syndrome [310][311][312][313][314][315][316].…”