Effects of the novel selective κ-opioid receptor agonist NP-5497-KA on morphine-induced reward-related behaviors.

Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the µ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3',5'-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1-10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1-10 µg/kg). Nalfurafine (10 µg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects.

Comparative Impact of Isolated Ultrafiltration and Hemodialysis on Fluid Distribution: A Bioimpedance Study.

INTRODUCTION: Isolated ultrafiltration (IUF) is an alternative treatment for diuretic-resistant patients with fluid retention. Although hemodialysis (HD) predominantly decreases extracellular water (ECW), the impact of IUF on fluid distribution compared with HD remains unclear. METHODS: We compared the effect of HD (n = 22) and IUF (n = 10) sessions on the body fluid status using a bioimpedance analysis device (InBody S10). RESULTS: The total ultrafiltration volume was similar between HD and IUF (HD 2.5 ± 0.3 vs. ICF 2.1 ± 0.3 L/session, p = 0.196). The reduction rate of ECW was significantly higher than that of intracellular water (ICW) after HD (ECW -7.9% ± 0.8% vs. ICW -3.0% ± 0.9%, p < 0.001) and IUF (ECW -5.8% ± 0.9% vs. ICW -3.6% ± 0.8%, p = 0.048). However, the change in the ratio of ECW to total body water in HD was significantly larger than that in IUF (HD -3.2% ± 0.3% vs. ICF -1.1% ± 0.4%, p < 0.001). The reduction rates in serum tonicity (effective osmolality) were higher after HD than after IUF (HD -1.8% ± 0.5% vs. IUF -0.6% ± 0.2%, p = 0.052). Among the components of effective osmolality, the reduction rates of serum K+ and glucose levels after HD were significantly higher than those after IUF (serum K+: HD -30.5% ± 1.6% vs. IUF -0.5% ± 3.8%, p < 0.001; serum glucose: HD -15.4% ± 5.0% vs. IUF 0.7% ± 4.8%, p = 0.026), while the serum Na+ level was slightly and similarly reduced (HD -0.8% ± 0.4% vs. IUF -0.8% ± 0.4%, p = 0.500). The reduction in the osmolal gap value (measured osmolality-calculated osmolarity) was significantly greater after HD sessions than after IUF sessions (HD -12.4 ± 1.4 vs. IUF 2.0 ± 1.0 mOsm/kg, p = 0.001). CONCLUSION: The extracellular fluid reduction effect of HD is stronger than that of IUF. The different changes in effective osmolality and osmolal gap after HD and IUF sessions may be related to the different effects of HD and IUF on fluid distribution.

Dysfunction of blood pressure regulation in hyperhomocyteinemia model in rats.

Hyperhomocysteinemia (HHC) has been reported to be one of risk factors for cardiovascular disease. We investigated the effects of HHC on blood pressure regulation and its association with damage to the thoracic aorta and imbalance of redox in plasma in rats. Rats were fed a methionine enriched diet (Met diet) or a methionine and cholesterol (Met+Chol diet) enriched diet for 16 weeks to create a subchronic HHC model, in which the plasma concentration of homocysteine was about 7 times higher than that of control rats. The increase in systolic blood pressure (Δ-SBP) from sympathetic stimulation by L-epinephrine was 2- to 3-fold larger in HHC model in rats than that in control rats after several weeks of the treatment. These findings suggest that HHC deteriorates vaso-regulatory function, which could bring on an increased risk of cardiovascular events in humans. In addition, some of the elastic lamellae in the aorta were disrupted in the HHC group. However, the content of cross-linkages which give elasticity and mechanical strength in the lamellae, was not significantly different between HHC and control rats. Also plasma concentrations of thiobarbituric acid reactive substance and glutathione as indicators for redox balance in plasma were not different. In conclusion, the deterioration of vaso-regulation in HHC model in rats might be caused by the damage to elastic lamellae in the aorta, and not by oxidative stresses.

Disruption of elastic lamellae in the aorta by D-penicillamine and its effect on vaso-regulation in rats.

We assessed the effects of D-penicillamine (D-PA) on cross-linkages in elastin and vaso-regulatory function in rats. After administration of D-PA at a dose of 100 mg/kg/day for 7 weeks to adult and young rats, the thoracic aortas were isolated. The elastic lamellae in the aorta were disrupted histopathologically in all the treated groups. The content of cross-linkages in elastin, i.e. desmosine and isodesmosine, which gives elasticity to the aortic wall, was significantly reduced in the D-PA treated groups versus the control groups. On the other hand, the content of pyridinoline as a marker of insoluble collagen was significantly reduced in the D-PA treated groups, even though the total collagen content was not changed. In addition, after 7 weeks of treatment with D-PA, the change between systolic blood pressure before and after sympathetic stimulation (Δ-SBP) by L-epinephrine was about 2.5-fold larger than that in the control group. Similar results were obtained using angiotensin II or ouabain instead of L-epinephrine. These findings demonstrated that D-PA disrupted elastic lamellae of the rat aorta by reduction of the cross-linkages in elastin and collagen, which caused dysfunction of vaso-regulation. Also, they suggested the possibility that long-term treatment with D-PA in patients could cause a decrease in vaso-regulatory function and could increase the risk of cardiovascular events.

Disruption of elastic lamellae in aorta and dysfunction of vaso-regulation by rofecoxib in rats.

We assessed the effects of rofecoxib on cross-linkage formation in elastin and vaso-regulatory function in rats. After administration of rofecoxib at a dose of 10 mg/kg for 7 weeks to young rats and for 7 and 10 weeks to adult rats, thoracic aortas were isolated. The elastic lamellae in the aortas were disrupted histopathologically in all the treated groups. However, the content of cross-linkages in elastin, i.e. desmosine and isodesmosine, which give elasticity to the aortic wall, was not significantly different between the rofecoxib treated and control groups. On the other hand, although the baseline blood pressure was not changed during the treatment period in both young and adult rats, after several weeks of treatment with rofecoxib the change between systolic blood pressure before and after sympathetic stimulation by L-epinephrine was 2 to 3-fold larger than that in the control group. Similar results were obtained using angiotensin II instead of L-epinephrine. The exposure to rofecoxib (area under the plasma concentration-time curve) of rats after single administration was a few times higher than that of humans in clinical use. These findings indicate that rofecoxib did not directly inhibit formation of cross-linkages in elastin of the aorta in rats. However, the treatment with rofecoxib for several weeks disrupted elastic lamellae and caused depression of vaso-regulatory function in rats, which could bring on an increased risk of cardiovascular events in human.