U-50,488, a selective kappa opioid agonist: Comparison to other reputed kappa agonists

doi:10.1016/S0278-5846(82)80130-9

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Volume 6, Issues 4–6, 1982, Pages 467-470

https://doi.org/10.1016/S0278-5846(82)80130-9 Get rights and content

Abstract

1.
U-50,488 is a structurally novel, non-mu opioid. In the present experiments it was compared to the reputed kappa opioid agonists, ketazocine, ethylketocyclazocine and bremazocine as regards analgesic cross tolerance to morphine and U-50,488, antagonism of analgesia by naloxone and MR-2266 (in vivo pA₂ determination), and narcotic antagonist properties (antagonism of morphine analgesia and precipitation of abstinence in morphine-dependent mice).
2.
The analgesic mechanism of bremazocine was similar to that of U-50,488 but the former compound had, in addition, considerable mu-antagonist activity. The analgesic mechanisms of the ketazocines were less selective; both shared both mu and kappa agonist properties. U-50, 488, however, had no such mu agonist or antagonist effects and thus is a more selective agonist.
3.
This compound and its congeners may prove useful in the elucidation of the functions of kappa receptors in the central nervous system.

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Citation Excerpt :
Intra-amygdala administration of p38 inhibitor SB203580 significantly inhibited p38 MAPK activation and completely blocked U50,488H-induced conditioned place aversion. We chose U50,488H as κ opioid receptor agonist to detect the mechanism of κ opioid receptor activation-induced aversive effect, as U50,488H is a classic and selective κ opioid receptor agonist (Von Voigtlander and Lewis, 1982). In the place conditioning procedure, we found that systemic administration of U50,488H induced significant conditioned place aversion, which was consistent with previous results showing that κ opioid receptor activation was involved in aversive emotion (Mucha and Herz, 1985; Bals-Kubik et al., 1993).
κ opioid receptor agonists produce aversive effects in rodents, however the underlying mechanisms remain unclear. Activation of p38 mitogen-activated protein kinase (MAPK) has been discovered to play a critical role in the modulation of affective behaviors. The present study was undertaken to detect the possible involvement of p38 MAPK in the aversive effects induced by κ opioid receptor activation. We found that the κ opioid receptor agonist trans-(±)-3,4-Dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzenacetamide methanesulfonate salt (U50,488H) produced significant place aversion in mice as measured by the conditioned place preference procedure, accompanied with significant p38 MAPK activation in the amygdala, but not in the nucleus accumbens and hippocampus. Stereotaxic microinjection of the p38 MAPK inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridy-l)-1H-imidazole (SB203580) into amygdala significantly inhibited p38 MAPK activation and completely blocked the conditioned place aversion in mice. Thus, these results suggested that activation of p38 MAPK in the amygdala was required to mediate κ opioid receptor-induced aversive behavior.
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Original PaperU-50,488, a selective kappa opioid agonist: Comparison to other reputed kappa agonists

Life Sci.

4-Amino-4-arylcyclohexanones and their derivatives, a novel class of analgesics. 1. Modification of the aryl ring

J. Med. Chem.

Endogenous opioid peptides: multiple agnoists and receptors

Nature

Original Paper
U-50,488, a selective kappa opioid agonist: Comparison to other reputed kappa agonists