Analgesic Effects of Different κ-Receptor Agonists Used in Daytime Laparoscopic Cholecystectomy

Background. Comparing the effect of two different κ-receptor agonists, nalbuphine and oxycodone, and regular morphine in patients for prophylactic analgesia of acute pain after daytime laparoscopic cholecystectomy. Methods. One hundred and twenty-four patients undergoing laparoscopic cholecystectomy were randomly allocated to receive nalbuphine (group N), oxycodone (group O), and morphine (group M). The three groups were all given intravenous injection (iv.) of 0.15 mg/kg injection before incision and 0.05 mg/kg injection at the end of pneumoperitoneum. The Visual Analogue Scale (VAS) scores (incision, visceral, and shoulder) and Ramsay sedation scores at 1, 2, 4, 8, 12, 16, 20, and 24 hours after surgery, the time of extubation, the incidence of postoperative adverse events, the satisfaction of pain treatment, and the duration of stay after surgery were all recorded. Results. Compared with group M, the VAS scores of visceral pain at rest decreased in group N and group O at 1-8 h after surgery ( P < 0.05 ). The VAS scores of visceral pain at movement in group N decreased longer than those in group O ( P < 0.05 ). Compared with that of group M, the postoperative time in Ramsay sedation score of group O increased longer than that of group N ( P < 0.05 ). Compared with group N, patients had worse sleep quality in group O, longer length of stay in group M, and lower satisfaction in both groups. Conclusion. Compared with morphine, prophylactic use of the κ-receptor agonists, nalbuphine and oxycodone, during laparoscopic cholecystectomy can reduce postoperative visceral pain. Furthermore, the nalbuphine group had fewer adverse reactions, better analgesia, and better satisfaction.

Activation of peripheral opioid κ1 receptor prevents cardiac reperfusion injury

The role of opioid κ1 and κ2 receptors in reperfusion cardiac injury was studied. Male Wistar rats were subjected to a 45-min coronary artery occlusion followed by a 120-min reperfusion. Opioid κ receptor agonists were administered intravenously 5 min before the onset of reperfusion, while opioid receptor antagonists were given 10 min before reperfusion. The average value of the infarct size/area at risk (IS/AAR) ratio was 43 – 48 % in untreated rats. Administration of the opioid κ1 receptor agonist (-)-U-50,488 (1 mg/kg) limited the IS/AAR ratio by 42 %. Administration of the opioid κ receptor agonist ICI 199,441 (0.1 mg/kg) limited the IS/AAR ratio by 41 %. The non-selective opioid κ receptor agonist (+)-U-50,488 (1 mg/kg) with low affinity for opioid κ receptor, the peripherally acting opioid κ receptor agonist ICI 204,448 (4 mg/kg) and the selective opioid κ2 receptor agonist GR89696 (0.1 mg/kg) had no effect on the IS/AAR ratio. Pretreatment with naltrexone, the peripherally acting opioid receptor antagonist naloxone methiodide, or the selective opioid κ receptor antagonist nor-binaltorphimine completely abolished the infarct-reducing effect of (-)-U-50,488 and ICI 199,441. Pretreatment with the selective opioid δ receptor antagonist TIPP[ψ] and the selective opioid µ receptor antagonist CTAP did not alter the infarct reducing effect of (-)-U-50,488 and ICI 199,441. Our study is the first to demonstrate the following: (a) the activation of opioid κ2 receptor has no effect on cardiac tolerance to reperfusion; (b) peripheral opioid κ1 receptor stimulation prevents reperfusion cardiac injury; (c) ICI 199,441 administration resulted in an infarct-reducing effect at reperfusion; (e) bradycardia induced by opioid κ receptor antagonists is not dependent on the occupancy of opioid κ receptor.

Profile of a short-acting κ-antagonist, LY2795050, on self-grooming behaviors, forced swim test and locomotor activity: sex comparison in mice

Background: Novel short-acting κ(kappa)-opioid receptor selective antagonists are translational tools to examine the impact of the κ-receptor/dynorphin system in assays related to central nervous system dysfunction (e.g., substance use disorders, anhedonia and depression). The effects of such compounds have been compared in males and females under very limited conditions. Aims: The goal of this study was to examine potential sex differences in the effects of a κ-agonist and a short-acting κ-antagonist in an ethologically relevant test of anhedonia, the “splash test” of self-grooming, and also in the forced swim test and in locomotor activity. Methods: We examined the dose-dependence of grooming deficits caused by the κ-agonist U50,488 (0.1–3.2 mg/kg intraperitoneal (i.p.)) in gonadally intact adult male and female C57BL/6J mice. We then compared the effects of the short-acting κ-antagonist LY2795050 ((3-chloro-4-(4-(((2S)-2-pyridin-3-ylpyrrolidin-1-yl)methyl) phenoxy)benzamide)); 0.032–0.1 mg/kg i.p.) in blocking grooming deficits caused by U50,488 (3.2 mg/kg). The effects of LY2795050 were also studied in the forced swim test (FST). The effects of LY2795050 in blocking the locomotor depressant effects of U50,488 (10 mg/kg) were also studied. Results: U50,488 produced dose-dependent grooming deficits in male and female mice, and LY2795050 prevented these effects. In contrast, LY2795050 decreased immobility in the FST in males at a dose of 0.1 mg/kg, but not in females, up to a dose of 0.32 mg/kg. Also, LY2795050 (0.32 mg/kg) prevented and also reversed the locomotor-depressant effects of U50,488 (10 mg/kg), in males and females. Conclusions: This study further implicates the κ-receptor system in ethologically relevant aspects of anhedonia, and confirms sexual dimorphism in some behavioral effects of novel κ-antagonists.

Analgesic Effect Comparison Between Nalbuphine and Sufentanil for Patient-Controlled Intravenous Analgesia After Cesarean Section

Background: Efficient maternal pain relief after cesarean delivery remains challenging, but it is important to improve outcomes for the mother and the newborn during the puerperium. We compared the analgesic effect of nalbuphine (a κ receptor agonist/μ receptor antagonistic) with that of sufentanil (a µ-receptor agonist) in patient-controlled intravenous analgesia (PCIA) after cesarean section.Methods: We enrolled 84 patients scheduled for elective cesarean sections with spinal anesthesia and randomized them into either nalbuphine or sufentanil groups (42 patients each). Pain scores, PCIA drug consumptions, degree of satisfaction, and adverse events were recorded as outcome measures.Results: The pain scores at rest and uterine cramping pain scores in the nalbuphine group were lower than those in the sufentanil group at 6, 12, and 24 h after the operation. Also, the pain scores while switching to a seated position were lower in the nalbuphine group than in the sufentanil group at 6 and 12 h after the operation (p &lt; 0.05). We found no significant differences in the PCIA drug consumption between the two groups. The degree of satisfaction in patients in the nalbuphine group was higher than that of patients in the sufentanil group (p = 0.01). Adverse events did not differ in the two groups.Conclusion: PCIA with nalbuphine provides better analgesia and higher patient satisfaction than sufentanil after cesarean section.

Effects of polar κ receptor agonists designed for the periphery on ATP-induced Ca2+ release from keratinocytes

The very polar pyridylmethyl derivative 5a (log D7.4 = 1.1) represents a potent and selective full κ-opioid receptor agonist (Ki = 0.13 nM, EC50 = 33 nM), which reduced the release of Ca2+-ions into the cytoplasm in human keratinocytes.

Novel Molecular Targets of Dezocine and Their Clinical Implications

Background: Although dezocine is a partial μ-opioid receptor agonist, it is not a controlled substance. Thus, the characterization of the molecular targets of dezocine is critical for scientific and clinical implications. The goal of this study is to characterize molecular targets for dezocine and determine their implications. Methods: A binding screen for dezocine was performed on 44 available receptors and transporter proteins. Functional assays for the novel targets were performed along with computation calculations to locate the binding site. A G protein activation study was performed for the human κ opioid receptor to determine whether dezocine is a κ-antagonist. Data are presented as mean ± standard error. Results: The affinities for dezocine were 3.7 ± 0.7 nM for the μ receptor, 527 ± 70 nM for the δ-receptor, and 31.9 ± 1.9 nM for the κ-receptor. Dezocine failed to induce G protein activation with κ-opioid receptor and concentration dependently inhibited κ-agonist (salvinorin A and nalbuphine)–induced receptor activation, indicating that dezocine is a κ-antagonist. Two novel molecular targets (norepinephrine transporter and serotonin transporter) were identified. Dezocine concentration-dependently inhibited norepinephrine and serotonin reuptake in vitro. The half maximal inhibitory concentrations (expressed as pIC50) were 5.68 ± 0.11 for norepinephrine transporter and 5.86 ± 0.17 for serotonin transporter. Dezocine occupied the binding site for known norepinephrine transporter and serotonin transporter inhibitors. Conclusions: The unique molecular pharmacological profile of dezocine as a partial μ-receptor agonist, a κ-receptor antagonist, and a norepinephrine and serotonin reuptake inhibitor (via norepinephrine transporter and serotonin transporter) was revealed. These discoveries reveal potentially important novel clinical implications and drug interactions of dezocine.