nalbuphine and Disease-Models--Animal

Antipruritic effects of kappa opioid receptor (KOR) agonists have been shown in rodent models of acute and chronic scratching (itchlike behavior). Three KOR agonists, nalfurafine, difelikefalin, and nalbuphine, are in clinical studies for antipruritic effects in chronic itch of systemic and skin diseases. Nalfurafine (in Japan) and difelikefalin (in the USA) were approved to be used in the treatment of chronic itch in hemodialysis patients. The FDA-approved nalbuphine has been used in clinic for over 40 years, and it is the only narcotic agonist that is not scheduled. We aimed to study (a) antiscratch activity of nalbuphine against TAT-HIV-1 protein (controls HIV transcription)-, deoxycholic acid (DCA, bile acid)-, and chloroquine (CQ)-induced scratching in a mouse model of acute itch; and (b) whether the effect of nalbuphine is produced via KORs. First, dose-responses were developed for pruritogens. Mice were pretreated with nalbuphine (0.3-10 mg/kg) and then a submaximal dose of pruritogens were administered and the number of scratching bouts was counted. To study if the antiscratch effect of nalbuphine is produced via KOR, we used KOR knock out mice and pharmacologic inhibition of KORs using nor-binaltorphimine, a KOR antagonist. For this aim, we used CQ as a pruritogen. We found that: (a) TAT-HIV-1 protein elicits scratching in a dose-dependent manner; (b) nalbuphine inhibits scratching induced by TAT-HIV-1, DCA, and CQ dose-dependently; and (c) nalbuphine inhibits scratching induced by CQ through KORs. In conclusion, nalbuphine inhibits scratching elicited by multiple pruritogens.

Topics: Animals; Antipruritics; Behavior, Animal; Chloroquine; Deoxycholic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Nalbuphine; Naltrexone; Narcotic Antagonists; Pruritus; Receptors, Opioid, kappa; tat Gene Products, Human Immunodeficiency Virus

Cancer pain is a debilitating disorder of human breast cancer and a primary determinant of the poor quality of life, and relieving pain is fundamental strategy in the cancer treatment. However, opioid analgesics, like morphine and fentanyl, which are widely used in cancer pain treatment have been reported to enhance stem-like traits and epithelial-mesenchymal transition (EMT) of breast cancer cells. As such, it is vital to make the best choice of analgesic for breast cancer management.. MTT assays and colony formation assays were performed to examine tumor cell proliferation upon nalbuphine treatment. RT-PCR, western blot, flow cytometry, sphere formation, immunohistochemistry, transwell assays, wound healing assays and mouse xenograft were used to assess the biological effects of nalbuphine treatment.. Nalbuphine inhibited breast cancer cell growth and tumorigenesis, with little effect on noncancerous breast cell lines. Nalbuphine suppressed cancer stem-like traits and EMT in both breast cancer cells and mouse xenograft tumor tissues. Additionally, activation of AKT reversed the nalbuphine-induced inhibition of cancer stem-like properties, tumorigenesis and EMT.. Our results demonstrate a new role of nalbuphine in inhibiting cancer stem-like properties and EMT in addition to relieving pain, which suggests that nalbuphine may be effective in breast cancer treatment.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Epithelial-Mesenchymal Transition; Female; Humans; Mice; Nalbuphine; Neoplastic Stem Cells; NF-kappa B; Proto-Oncogene Proteins c-akt; Signal Transduction; Xenograft Model Antitumor Assays

Effective medical management of levodopa-induced dyskinesia (LID) remains an unmet need for patients with Parkinson disease (PD). Changes in opioid transmission in the basal ganglia associated with LID suggest a therapeutic opportunity. Here we determined the impact of modulating both mu and kappa opioid receptor signaling using the mixed agonist/antagonist analgesic nalbuphine in reducing LID and its molecular markers in the nonhuman primate model.. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques with advanced parkinsonism and reproducible LID received a range of nalbuphine doses or saline subcutaneously as: (1) monotherapy, (2) acute coadministration with levodopa, and (3) chronic coadministration for 1 month. Animals were assessed by blinded examiners for motor disability and LID severity using standardized rating scales. Plasma levodopa levels were determined with and without nalbuphine, and postmortem brain samples were subjected to Western blot analyses.. Nalbuphine reduced LID in a dose-dependent manner by 48% (p < 0.001) without compromising the anti-PD effect of levodopa or changing plasma levodopa levels. There was no tolerance to the anti-LID effect of nalbuphine given chronically. Nalbuphine coadministered with levodopa was well tolerated and did not cause sedation. Nalbuphine monotherapy had no effect on motor disability. Striatal tissue analyses showed that nalbuphine cotherapy blocks several molecular correlates of LID, including overexpression of ΔFosB, prodynorphin, dynorphin A, cyclin-dependent kinase 5, and increased phosphorylation of DARPP-32 at threonine-34.. Nalbuphine reverses the molecular milieu in the striatum associated with LID and is a safe and effective anti-LID agent in the primate model of PD. These findings support repurposing this analgesic for the treatment of LID.

Topics: Analgesics, Opioid; Animals; Antiparkinson Agents; Disease Models, Animal; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Female; Levodopa; Macaca; Male; Nalbuphine; Neostriatum; Parkinson Disease; Receptors, Opioid, kappa; Receptors, Opioid, mu

Anti-nociceptive and anti-inflammatory effects of methanolic extract of Wrightia arborea (MEWA) were examined using different models in rats. MEWA was given to rats orally upto 2000 mg kg(-1) b.wt. for acute toxicity study and observed for 14 days. Anti-nociceptive activity was evaluated in rats against Acetic acid induced writhing (chemically induced pain) and Tail immersion method (thermally induced pain). Acute anti-inflammatory activity of MEWA was also evaluated in Formaline-induced rat paw edema model and Carrageenan-induced hind paw edema model in rats. Results demonstrated that no mortality was found upto single dose of 2000 mg kg(-1) b.wt. in rats even after 14 days observation. In comparison to control group MEWA at 100 and 200 mg kg(-1) b.wt. showed highly significant anti-nociceptive activity against chemically (p < 0.001) as well as thermally (p < 0.05 and p < 0.001) induced pain as compared to standard drugs, indomethacin and nalbufin, respectively. In the formalin test, both the doses of 100 and 200 mg kg(-1) of extract significantly prevented increase in volume of paw edema (p < 0.05 and p < 0.01) both in the neurogenic and inflammatory phases. MEWA (200 and 400 mg kg(-1) p.o.) also significantly prevented increase in volume of paw edema in Carrageenan test (p < 0.05 and p < 0.001). The results suggest that MEWA has significant analgesic and anti-inflammatory potential which may be mediated by central and peripheral mechanism.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Apocynaceae; Disease Models, Animal; Edema; Female; Indomethacin; Inflammation; Male; Methanol; Nalbuphine; Pain; Phytotherapy; Plant Components, Aerial; Plants, Medicinal; Rats; Solvents

In opioid-dependent subjects, the low-efficacy mu agonist nalbuphine generally precipitates withdrawal or withdrawal-like stimulus effects. To provide a more complete characterization of the discriminative stimulus effects of nalbuphine in opioid-treated subjects, seven White Carneux pigeons were treated daily with 10 mg/kg morphine i.m. and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine, and saline by responding on one of three different keys. When tested, morphine produced morphine-key responding and nalbuphine produced nalbuphine-key responding. Replacing the daily morphine injection with saline produced nalbuphine-key responding, and this effect was reversed by the administration of morphine. In substitution tests with other compounds, the antagonists naltrexone (i.m.) and CTAP (D-Phe-Cys-Tyr-D-Tryp-Lys-Thr-Pen-Thr-NH2) (i.c.v.) produced nalbuphine-key responding. High-efficacy agonists fentanyl and etorphine produced morphine-key responding. The intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol produced a pattern of morphine-, saline-, and/or nalbuphine-key responding that differed across individual pigeons. The lower efficacy agonists nalorphine and levallorphan produced predominantly nalbuphine-key responding. The kappa agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy micro agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment.

Topics: Animals; Columbidae; Conditioning, Operant; Discrimination Learning; Disease Models, Animal; Morphine; Morphine Dependence; Nalbuphine; Narcotics; Sodium Chloride

Recent evidence has suggested a relationship between the endogenous opioid peptides and the pathophysiology of various shock states. In the present study, we investigated the relationship between the effectiveness of naloxone (an opiate antagonist) and nalbuphine (an opiate agonist/antagonist), and the changes in circulating levels of catecholamines in the nonhuman primate subjected to hemorrhagic shock. Plasma levels of catecholamines were measured using high-performance liquid chromatography (HPLC) during hemorrhagic shock in 15 female baboons. Plasma levels of both epinephrine and norepinephrine increased significantly during hemorrhagic shock (p less than 0.05), which correlated with an increase in heart rate. Bolus administration of naloxone (5 mg/kg) significantly increased both plasma epinephrine (p less than 0.01) and norepinephrine (p less than 0.05) over shock levels along with a transient but significant increase in cardiac output (p less than 0.05) and mean arterial pressure (p less than 0.05), and a significant decrease in heart rate (p less than 0.05). Improvements in hemodynamics were maintained with a constant infusion of naloxone (5 mg/kg/hr), which also caused a further significant increase in plasma epinephrine (p less than 0.01). Administration of a single bolus of the opiate agonist/antagonist nalbuphine (5 mg/kg) dramatically decreased cardiac output and mean arterial pressure and had no effect on circulating catecholamines. Our results suggest that (1) the beneficial action of high-dose naloxone in primate hemorrhagic shock may be attributable in part to a drug-induced increase in circulating endogenous catecholamines; and (2) the failure of high-dose nalbuphine to improve cardiovascular function may be related to its partial agonist (cardiodepressant) properties at higher doses.

Topics: Animals; Catecholamines; Disease Models, Animal; Female; Hemodynamics; Morphinans; Nalbuphine; Naloxone; Papio; Shock, Hemorrhagic