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kappa opioid

Rita Turnaturi, Carmela Parenti, Orazio Prezzavento, Agostino Marrazzo, Paschalina Pallaki, Zafiroula Georgoussi, Emanuele Amata, Lorella Pasquinucci
The opioid pharmacological profile of cis -(-)- N -normetazocine derivatives is deeply affected by the nature of their N -substituents. Here, our efforts were focused on the synthesis and pharmacological evaluation of novel derivatives of the lead LP1, a multitarget opioid analgesic compound featuring an N -phenylpropanamido substituent. LP1 derivatives 5a - d and 6a - d were characterized by flexible groups at the N -substituent that allow them to reposition themselves relative to cis -(-)- N -normetazocine nucleus, thus producing different pharmacological profiles at the mu, delta and kappa opioid receptors (MOR, DOR and KOR) in in vitro and in vivo assays...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Jenny L Wilkerson, Zachary A Curry, Pamela D Kinlow, Brittany L Mason, Ku-Lung Hsu, Mario van der Stelt, Benjamin F Cravatt, Aron H Lichtman
A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (i.e., pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury of the sciatic nerve (CCI) elicits common pain-stimulated responses (i.e., mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within one week...
March 8, 2018: Pain
Rachel I Anderson, David E Moorman, Howard C Becker
Understanding the neural systems that drive alcohol motivation and are disrupted in alcohol use disorders is of critical importance in developing novel treatments. The dynorphin and orexin/hypocretin neuropeptide systems are particularly relevant with respect to alcohol use and misuse. Both systems are strongly associated with alcohol-seeking behaviors, particularly in cases of high levels of alcohol use as seen in dependence. Furthermore, both systems also play a role in stress and anxiety, indicating that disruption of these systems may underlie long-term homeostatic dysregulation seen in alcohol use disorders...
March 11, 2018: Handbook of Experimental Pharmacology
Lin Zhou, Yahui Hu, Chengyuan Li, Yunyi Yan, Luyao Ao, Boyang Yu, Weirong Fang, Jihua Liu, Yunman Li
Vincristine is a commonly used chemotherapeutic drug that can produce painful peripheral neuropathy. The chemokine (C-X-C motif) ligand 1 (CXCL1) and its receptor chemokine (C-X-C motif) receptor 2 (CXCR2) may mediate the resolution of this inflammation. In this study, we investigated whether and how CXCL1 contributes to vincristine-induced pain and the underlying mechanisms of levo-corydalmine (l-CDL, a tetrahydroprotoberberine). Oxycodone hydrochloride (a semisynthetic opioid analgesic) was used as positive control in vivo experiments...
March 5, 2018: Neuropharmacology
Justyna Piekielna-Ciesielska, Adriano Mollica, Stefano Pieretti, Jakub Fichna, Agata Szymaszkiewicz, Marta Zielińska, Radzisław Kordek, Anna Janecka
Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH2 (C-36) and Dmt-c[D-Lys-Phe-p-CF3 -Phe-Asp]NH2 (F-81)...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
Yan Zhou, Rachel Crowley, Thomas Prisinzano, Mary Jeanne Kreek
Alcohol relapse plays a major role in alcohol dependence and is an important focus for the treatment of alcoholism. The alcohol deprivation effect (ADE) is a widely used paradigm in rodents to model the relapse episodes that occur in human alcoholics. Mesyl Salvinorin B (MSB) is a potent and selective kappa opioid receptor (KOP-r) full agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists and a longer duration of action in mice than the structurally similar salvinorin A...
February 26, 2018: Neuroscience Letters
Abigail Laman-Maharg, Alexia V Williams, Mikaela D Zufelt, Vanessa A Minie, Stephanie Ramos-Maciel, Rebecca Hao, Evelyn Ordoñes Sanchez, Tiffany Copeland, Jill L Silverman, Angelina Leigh, Rodney Snyder, F Ivy Carroll, Timothy R Fennell, Brian C Trainor
There is growing evidence that kappa opioid receptor (KOR) antagonists could be a useful class of therapeutics for treating depression and anxiety. However, the overwhelming majority of preclinical investigations examining the behavioral effects of KOR antagonists have been in male rodents. Here, we examined the effects of the long-acting KOR antagonist nor-binaltophimine (norBNI) on immobility in the forced swim test in males and females of two different rodent species (C57Bl/6J and California mice). Consistent with previous reports, norBNI (10 mg/kg) decreased immobility in the forced swim test for male C57Bl/6J and California mice...
2018: Frontiers in Pharmacology
Jacqueline M Cohen, Mollie E Wood, Sonia Hernandez-Diaz, Hedvig Nordeng
PURPOSE: Father's medication use is of interest in fertility studies and as negative control exposures in pregnancy medication safety studies. We sought to compare self-report to prescription records to understand how reliably each of these sources of information may be used. METHODS: We compared self-reported medication use in the 6 months prior to pregnancy from fathers participating in the Norwegian Mother and Child Cohort Study to records of dispensed prescriptions from the Norwegian Prescription Database that overlapped in time...
February 28, 2018: Pharmacoepidemiology and Drug Safety
Toshiya Matsuzaki, Altankhuu Tungalagsuvd, Munkhsaikhan Munkhzaya, Takeshi Iwasa, Kiyohito Yano, Yiliyasi Mayila, Takako Tokui, Rie Yanagihara, Sumika Matsui, Takeshi Kato, Akira Kuwahara, Minoru Irahara
Kisspeptin/neurokinin B (NKB)/dynorphin (Dyn) (KNDy) neuron in hypothalamic arcuate nucleus plays a key role in GnRH/LH pulsatile secretion. We aimed to determine whether stimulation of NKB/neurokinin 3 receptor (NK3R) signaling and inhibition of Dyn/kappa-opioid receptor (KOR) signaling recover LH secretion that is suppressed by acute fasting in male rats. Furthermore, we determined dose dependent effect of NKB/NK3R signaling on serum LH level under acute fasting condition in male mice. Mature male rats were injected saline (0...
February 23, 2018: Endocrine Journal
Jasper A Heinsbroek, Amelia B Furbish, Jamie Peters
Kappa opioid receptor (KOR) agonists have known anti-addiction properties and can reduce drug seeking. Their potential for clinical use has largely been daunted by their aversive properties mediated through p38 MAPK signaling. Here we examined the therapeutic potential of the KOR agonist U50,488 (U50) to reduce cocaine seeking in a self-administration model. Following cocaine self-administration and 7 days of forced home-cage abstinence, rats were administered a single dose of U50 (5 mg/kg, i.p.) 30 min prior to the first extinction training session, wherein cocaine and the discrete cocaine-paired cues were no longer available...
February 22, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Kornél Király, Márk Kozsurek, Erika Lukácsi, Benjamin Barta, Alán Alpár, Tamás Balázsa, Csaba Fekete, Judit Szabon, Zsuzsanna Helyes, Kata Bölcskei, Valéria Tékus, Zsuzsanna E Tóth, Károly Pap, Gábor Gerber, Zita Puskár
Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states...
February 22, 2018: Scientific Reports
E Domi, E Barbier, E Augier, G Augier, D Gehlert, R Barchiesi, A Thorsell, L Holm, M Heilig
Prior work suggests a role of kappa-opioid signaling in the control of alcohol drinking, in particular when drinking is escalated due to alcohol-induced long-term neuroadaptations. Here, we examined the small molecule selective kappa antagonist CERC-501 in rat models of alcohol-related behaviors, with the objective to evaluate its potential as a candidate therapeutic for alcohol use disorders. We first tested the effect of CERC-501 on acute alcohol withdrawal-induced anxiety-like behavior. CERC-501 was then tested on basal as well as escalated alcohol self-administration induced by 20% alcohol intermittent access...
February 5, 2018: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
Belin G Teklezgi, Annapurna Pamreddy, Sooraj Baijnath, Hendrik G Kruger, Tricia Naicker, Nirmala D Gopal, Thavendran Govender
Opioid addiction is a serious public health concern with severe health and social implications; therefore, extensive therapeutic efforts are required to keep users drug free. The two main pharmacological interventions, in the treatment of addiction, involve management with methadone an mu (μ)-opioid agonist and treatment with naltrexone, μ-opioid, kappa (κ)-opioid and delta (δ)-opioid antagonist. MET and NAL are believed to help individuals to derive maximum benefit from treatment and undergo a full recovery...
February 14, 2018: Addiction Biology
Blaine A Jacobs, Miryam M Pando, Elaine Jennings, Teresa A Chavera, William P Clarke, Kelly A Berg
There is abundant evidence for formation of G protein-coupled receptor heteromers in heterologous expression systems, but little is known of the function of heteromers in native systems. Heteromers of δ and κ opioid receptors (DOR-KOR heteromers) have been identified in native systems. We previously reported that activation of DOR-KOR heteromers expressed by rat pain-sensing neurons (nociceptors) produces robust, peripherally mediated antinociception. Moreover, DOR agonist potency and efficacy is regulated by KOR antagonists via allosteric interactions within the DOR-KOR heteromer in a ligand-dependent manner...
April 2018: Molecular Pharmacology
Shun Hirasawa, Min Cho, Tarsis F Brust, Jeremy J Roach, Laura M Bohn, Ryan A Shenvi
Salvinorin A (SalA) is a potent and selective agonist of the kappa-opioid receptor (KOR), but its instability has frustrated medicinal chemistry efforts. Treatment of SalA with weak bases like DBU leads to C8 epimerization with loss of receptor affinity and signaling potency. Here we show that replacement of C20 with H and replacement of O6 with CH2 stabilizes the SalA scaffold relative to its C8 epimer, so much so that epimerization is completely supressed. This new compound, O6C-20-nor-SalA, retains high potency for agonism of KOR...
January 31, 2018: Bioorganic & Medicinal Chemistry Letters
Todd Lingren, Senthilkumar Sadhasivam, Xue Zhang, Keith Marsolo
BACKGROUND AND AIM: Many clinical research studies claim to collect data that are also captured in the electronic medical record (EMR). We evaluate the potential for EMR data to replace prospective research data collection. METHODS: Using a dataset of 358 surgical patients enrolled in a prospective study, we examined the completeness and agreement of EMR and study entries for several variables, including the patient's stay in the post-operative care unit (PACU), surgical pain relief and pain medication side effects...
March 2018: International Journal of Medical Informatics
Raoul Belzeaux, Laurence Lalanne, Brigitte L Kieffer, Pierre-Eric Lutz
Substance use disorders (SUD) and behavioral addictions are devastating conditions that impose a severe burden on all societies, and represent difficult challenges for clinicians. Therefore, biomarkers are urgently needed to help predict vulnerability, clinical course, and response to treatment. Here, we elaborate on the potential for addiction biomarker discovery of the opioid system, particularly within the emerging framework aiming to probe opioid function in peripheral tissues. Mu, delta, and kappa opioid receptors all critically regulate neurobiological and behavioral processes that define addiction, and are also targeted by major pharmacotherapies used in the management of patients with SUD...
January 27, 2018: Trends in Molecular Medicine
Akhila Reddy, Amy Ng, Tarun Mallipeddi, Eduardo Bruera
Neuropathic pain in cancer patients is often difficult to treat, requiring a combination of several different pharmacological therapies. We describe two patients with complex neuropathic pain syndromes in the form of phantom limb pain and Brown-Sequard syndrome who did not respond to conventional treatments but responded dramatically to the addition of levorphanol. Levorphanol is a synthetic strong opioid that is a potent N-methyl-d-aspartate receptor antagonist, mu, kappa, and delta opioid receptor agonist, and reuptake inhibitor of serotonin and norepinephrine...
January 29, 2018: Journal of Palliative Medicine
Taylor Edwards, Nupur U Patel, Amy Blake, Samantha Prabakaran, Danielle Reimer, Steven R Feldman, Lindsay C Strowd
Atopic Dermatitis (AD) is a common chronic inflammatory skin disorder with a constellation of symptoms. Currently, there are numerous therapies in various phases of drug development that target the pathogenesis of AD. Areas covered: Our paper aims to examine small molecule therapies and other novel agents registered for clinical trial in the phase II and mainly phase III stages of development. A literature search using PubMed as well as was conducted. Clinical trial evidence of these novel agents was compiled and assessed...
February 2018: Expert Opinion on Pharmacotherapy
Katie A Edwards, Joshua J Havelin, Mary I Mcintosh, Haley A Ciccone, Kathlene Pangilinan, Ian Imbert, Tally M Largent-Milnes, Tamara King, Todd W Vanderah, John M Streicher
Breast cancer metastasizes to bone, diminishing quality of life of patients due to pain, fracture, and limited mobility. Cancer-induced bone pain (CIBP) is characterized as moderate to severe ongoing pain, primarily managed by Mu opioid agonists such as fentanyl. However, opioids are limited by escalating doses and serious side effects. One alternative may be kappa opioid receptor (KOR) agonists. There are few studies examining KOR efficacy on CIBP, while KOR agonists are efficacious in peripheral and inflammatory pain...
January 22, 2018: Journal of Pain: Official Journal of the American Pain Society
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