Kappa-opioid Receptor Agonist U-50488H Research Articles

P-28 * OPIOIDERGIC MODULATION OF ETHANOL INTAKE IN THE NUCLEUS ACCUMBENS OF ALCOHOL-PREFERRING AA RATS

The present study addressed the role of accumbal mu- and kappa-opioid receptors in ethanol intake using male AA rats trained to drink 10% (v/v) ethanol in a limited access paradigm. The mu-opioid receptor antagonist CTOP (0.3, 1, or 3 ug per side), the mu-opioid receptor agonist DAMGO (0.03, 0.1, or 0.3 ug), the kappa-opioid receptor agonist U50488H (0.3, 1, or 3 ug), and the kappa-opioid receptor antagonists JDTic (15 ug) and nor-binaltorphimine (3 ug) were injected bilaterally into the nucleus accumbens shell. In another experiment, rats received a single subcutaneous injection of JDTic (10 mg/kg) and the long-term effects of the treatment on ethanol intake were monitored. CTOP, DAMGO and U50488H failed to alter ethanol intake significantly, though CTOP (0.3 and 1 ug) tended to increase and DAMGO (0.1 ug) to decrease ethanol intake. There was a tendency for decreased ethanol intake 72 h after accumbal JDTic, while systemic JDTic decreased ethanol intake at 48 h and 96 h. These results support the notion that central mu- and kappa-opioid receptors participate in the control of voluntary ethanol intake. They also suggest that accumbal kappa-opioid receptors may have a more prominent role in ethanol intake than previously assumed.

Sigma‐1 receptor function is critical for both the discriminative stimulus and aversive effects of the kappa‐opioid receptor agonist U‐50488H

The present study was undertaken to identify possible similarities between the effects of kappa-opioid receptor agonist, N-methyl-D-aspartate-receptor antagonist, and sigma receptor agonist on the discriminative stimulus effects of U-50488H, and the possible involvement of sigma receptors in the discriminative stimulus and aversive effects of U-50488H. The kappa-opioid receptor agonist U-50488H produced significant place aversion as measured by the conditioned place preference procedure, and this effect was completely abolished by treatment with the putative sigma-1 receptor antagonist NE-100. In addition, phencyclidine (+)-SKF-10047 and (+)-pentazocine, which are sigma receptor agonists, generalized to the discriminative stimulus effects of U-50488H in rats that had been trained to discriminate between U-50488H (3.0 mg/kg) and saline. Furthermore, NE-100 significantly attenuated the discriminative stimulus effects of U-50488H and the U-50488H-like discriminative stimulus effects of phencyclidine. These results suggest that the sigma-1 receptor is responsible for both the discriminative stimulus effects and aversive effects of U-50488H.

Involvement of peripheral mu opioid receptors in scratching behavior in mice

Pruritus is a common adverse effect of opioid treatment. However, the mechanism by which pruritus is induced by opioid administration is unclear. In this study, we examined the effects of the intradermal injection of loperamide, a peripherally restricted opioid receptor agonist, on the itch sensation. When injected intradermally into the rostral part of the back in mice, loperamide elicited scratching behavior. We also examined the effects of the selective mu opioid receptor agonist [d-Ala 2, N-Me-Phe 4, Gly 5-ol]-enkephalin acetate (DAMGO), the selective delta opioid receptor agonist [d-Pen 2,5]-enkephalin (DPDPE), and the selective kappa opioid receptor agonist U-50488H on scratching behavior in mice in order to determine which subtype is involved in opioid-induced pruritus. Following intradermal injection into the rostral part of the back in mice, DAMGO elicited scratching behavior, while DPDPE and U-50488H did not. This suggests that peripheral mu opioid activation elicits the itch sensation. Next, we focused on the treatment of opioid-induced itch sensation without central adverse effects. Naloxone methiodide is a peripherally restricted opioid receptor antagonist. In the present study, naloxone methiodide significantly suppressed scratching behavior induced by loperamide and DAMGO. These findings suggest that mu opioid receptors play a primary role in peripheral pruritus and that naloxone methiodide may represent a possible remedy for opioid-induced itching.

Cardioprotection by kappa-opioid receptor agonist U50488H is mediated by opioidergic regulation but not by calcium current modulation

BackgroundBecause the κ-opioid receptor (OR) agonist U50488H stimulates opioidergic regulation and inhibits L-type Ca2+ channels, this study was aimed at assessing the roles of OR and L-type Ca2+ channels on U50488H-induced cardioprotection.MethodsLangendorff-perfused rat hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Isolated hearts were treated with U50488H with or without the κ-OR antagonist nor-binaltorphimine (nor-BNI) or the Ca2+ channels activator BAY K 8644. Infarct size was measured with 2,3,5-triphenyltetrazolium chloride staining.ResultsU50488H treatment at reperfusion: (1) significantly reduced infarct size (11.3 ± 1.3%) compared to control hearts (27.7 ± 1.1%, P < 0.001), an effect that was completely blocked by nor-BNI (24.0 ± 0.9%, P < 0.001 vs. U50488H) but not by BAY K 8644 (7.1 ± 1.7%, P > 0.05 vs. U50488H); (2) significantly increased left ventricular developed pressure (65.3 ± 4.8%) after 2 h of reperfusion compared to control hearts (44.8 ± 3.6%, P < 0.05), an effect that was abrogated by nor-BNI (40.5 ± 4.5%, P > 0.05 vs. control) but not by BAY K 8644 (64.3 ± 5.6%, P < 0.01 vs. control); and (3) significantly decreased heart rate (P < 0.01 vs. control), an effect that was completely abrogated by both nor-BNI and BAY K 8644.ConclusionsU50488H significantly limits myocardial infarction and stunning in isolated rat hearts after ischemia-reperfusion induction. The infarct size limitation and contractility improvement observed with U50488H treatment during reperfusion are entirely mediated by OR stimulation and not by Ca2+ channel modulation.

Effect of A Kappa-opioid Receptor Agonist U50488H Given at Early Reperfusion Phase in Isolated Rat Hearts

The experiment was performed to determine the role of κ-opioid receptor (OR) agonist U50488H given at early reperfusion. Methods:Isolated hearts were subjected to 30 minutes of regional ischemia and 120 minutes of reperfusion.Hearts were assigned randomly to one of the three groups:1) Control (n = 9), 2) U50-1 (n = 8); 1μM of U50488H, and 3) U50-10 (n = 8); 10μM of U50488H.U50488 was perfused for a period of 5 min before and 30 min after reperfusion. Results:U50488H significantly reduced infarct size as a percentage of ischemic area (12.2 ± 1.9% in U50-1 and 7.2 ± 1.7% in U50-10, P ＜ 0.001) compared to the control hearts (27.2 ± 1.2%). After 2 hrs of reperfusion, left ventricular developed pressure was significantly recovered by U50488H (62.6 ± 5.7% in U50-1 and 68.6 ± 4.7% in U50-10, P = 0.018 and 0.002, respectively) compared to the control (46.3 ± 4.4%).Rate-pressure product was improved by 10μM U50488H (62.3 ± 5.5%, P = 0.007) but not by 1μM U50488H (50.0 ± 4.1%) compared to the control (44.7 ± 4.5%).U50488H significantly increased the ＋dP/dtmax (77.9 ± 5.5% in U50-1 and 78.0 ± 4.3 in U50-10, P = 0.005 and 0.001 vs. control, respectively).The −dP/dtmin also improved by 10μM U50488H (64.7 ± 4.8%, P = 0.003) compared to control (47.0 ± 2.7%). Conclusions:U50488H given at early reperfusion phase reduces both infarct size and myocardial stunning in isolated rat hearts.

Modulation of systemic and renal haemodynamics by κ‐opioids in conscious lambs

The purpose of the present study was to determine the cardiovascular effects of the kappa-opioid receptor agonist U-50488H at two stages of postnatal maturation under physiological conditions. Experiments were carried out firstly to define systemic and renal haemodynamic responses to kappa-opioid receptor activation and, secondly, to determine whether these effects are altered during postnatal maturation. To investigate whether the responses to U-50488H resulted from receptor-dependent effects, responses to U-50488H were also tested in the presence of the specific kappa-opioid receptor antagonist 5'-guanidinonaltrindole (GNTI). Experiments were carried out in two groups of conscious, chronically instrumented lambs aged approximately 1 and approximately 6 weeks. Mean arterial pressure, mean venous pressure and renal blood flow (RBF) were measured for 30 min before and 90 min after i.v. injection of U-50488H or vehicle. Heart rate increased in both age groups of lambs within 10 min of U-50488H administration. Mean arterial pressure decreased for 50 min following U-50488H administration at 1 week but, in contrast, increased transiently at 10 min in 6-week-old lambs, returning to control levels by 20 min. In both age groups, there was a sustained decrease in RBF following U-50488H. The aforementioned responses to U-50488H were abolished by pretreatment with GNTI. These data provide the first measurements of systemic and renal haemodynamic responses to kappa-opioid receptor activation during postnatal maturation.

Presynaptic opioid receptors on dopaminergic nerves in the rabbit caudate nucleus: coupling to pertussis toxin-sensitive G-proteins and interaction with D2 autoreceptors?

Slices of the rabbit caudate nucleus, preincubated with [3H]dopamine and subjected to electrical field stimulation, were used (1) to investigate the involvement of G-proteins in the signal transduction of presynaptic D2 (auto)receptors and kappa-opioid receptors on dopaminergic axon terminals in this tissue and (2) to study a possible mutual interaction of these two presynaptic receptors. Pretreatment of the slices with either pertussis toxin (8 micrograms/ml; 18 h), or N-ethylmaleimide (30 microM, 30 min) significantly reduced the inhibitory effects of both the D2 agonist quinpirole and the kappa-opioid receptor agonist U-50488H on the [3H]overflow evoked by 36 pulses (2 ms, 24 mA, 0.3 Hz), suggesting the coupling of both receptors to G-proteins. Experiments designed to study possible interactions of these two presynaptic receptors were carried out under stimulation conditions (only 1 pulse), which strongly diminish interference of endogenous transmitters released in the tissue with modulatory effects of exogenous drugs. For instance, due to the presence of endogenous dopamine, quinpirole was much less potent during 36-pulse-than during 1-pulse field stimulation, whereas the D2 antagonist domperidone was almost without effect in the latter case. Using the 1-pulse stimulation paradigm, the concentration/response curve of quinpirole was unaffected in the presence of the half-maximal inhibitory concentration of U-50,488 H (0.1 microM). On the other hand, also quinpirole at its half-maximal inhibitory concentration (0.1 microM), hardly affected the concentration/response curve of U-50,488 H: only high concentrations of U-50,488 H (above 1 microM) seemed to be slightly less effective in the presence than in the absence of the D2 agonist.(ABSTRACT TRUNCATED AT 250 WORDS)