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Mu Agonist

Gregory N Ruegsegger, Jacob D Brown, M Cathleen Kovarik, Dennis K Miller, Frank W Booth
The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine 1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), 2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and 3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats...
October 12, 2016: Neuroscience
Jianguo Zhuang, Xiuping Gao, Franklin Gao, Fadi Xu
We tested the hypothesis that mu-opioid receptors (MORs) in the caudomedial nucleus tractus solitarius (cmNTS) are important for the ventilatory responses to stimulation of bronchopulmonary C-fibers (PCFs), the carotid body-mediated hypoxia, and hypercapnia independent of the carotid body. First, we used immunohistochemistry to map MORs distribution in the caudal medulla. Then we compared the effects of intra-cmNTS microinjection of DAMGO (a MOR agonist) with or without a combination of CTAP (a MOR antagonist) on the ventilatory responses to: 1) right atrial injection of capsaicin (to stimulation of PCFs) and 2) acute hypoxia (HVR, to stimulate the carotid body) in awake intact rats; and 3) hypercapnia (HCVR) in the carotid body ablated rats...
October 12, 2016: Respiratory Physiology & Neurobiology
Marcelina Jasmine Silva, Andrea Rubinstein
Buprenorphine, a semisynthetic thebaine derivative, is a unique opioid, as it has activity at multiple receptors, including mu (partial agonist), kappa (antagonist), OLR-1 (agonist), and delta (antagonist). Because buprenorphine's pharmacology is relatively complex, misconceptions about its actions are common. Most other opioids act solely or predominately as full mu receptor agonists. Common practice at many institutions calls for the cessation of regular buprenorphine use 48-72 hours prior to surgery. This practice is based on three foundational theories that have come from scant data about the properties of buprenorphine: (1) that buprenorphine is only a partial mu agonist and therefore is not a potent analgesic; (2) because buprenorphine has a ceiling effect on respiratory depression, it also has a ceiling effect on analgesia; and (3) that buprenorphine acts as a "blockade" to the analgesic effects of other opiates when coadministered due to its strong binding affinity...
October 13, 2016: Journal of Pain & Palliative Care Pharmacotherapy
Eiko Yokota, Yuko Koyanagi, Kiyofumi Yamamoto, Yoshiyuki Oi, Noriaki Koshikawa, Masayuki Kobayashi
The insular cortex (IC) plays a principal role in the regulation of pain processing. Although opioidergic agonists depress cortical excitatory synaptic transmission, little is known about opioidergic roles in inhibitory synaptic transmission. In the IC, the opioid receptors differentially regulate the excitatory propagation: agonists of the mu (MOR), delta (DOR), and kappa (KOR) exhibit suppressive, facilitative, and little effects, respectively. Thus, we aimed to examine the effects of opioid receptor agonists on unitary inhibitory postsynaptic currents (uIPSCs) in the IC...
October 7, 2016: Neuroscience
Xiao-Fei Wang, Elisabeth Barbier, Yi-Ting Chiu, Yi He, Jia Zhan, Guo-Hua Bi, Hai-Ying Zhang, Bo Feng, Lee-Yuan Liu-Chen, Jia Bei Wang, Zheng-Xiong Xi
: The etiology and pathophysiology underlying opioid tolerance and dependence are still unknown. Because mu opioid receptor (MOR) plays an essential role in opioid action, many vulnerability-related studies have focused on single nucleotide polymorphisms of MOR, particularly on A118G. In this study, we found that a single-point mutation at the MOR T394 phosphorylation site could be another important susceptive factor in the development of opioid tolerance and dependence in mice. T394A mutation, in which a threonine at 394 was replaced by an alanine, did not alter agonist binding to MOR and opioid analgesia, but resulted in loss of etorphine-induced MOR internalization in spinal dorsal horn neurons and opioid analgesic tolerance induced by either morphine or etorphine...
October 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Laura C Sullivan, Teresa A Chavera, Raehannah J Jamshidi, Kelly A Berg, William P Clarke
Opioid receptors expressed by peripheral pain-sensing neurons are functionally inactive for antinociceptive signaling under most basal conditions, however, tissue damage or exposure to inflammatory mediators (e.g., bradykinin) converts these receptors from a non-responsive state to a functionally competent state. Here we tested the hypothesis that the basal, non-responsive state of the mu and delta opioid receptors (MOR and DOR, respectively) is the result of constitutive receptor activity that activates desensitization mechanisms, resulting in MOR and DOR receptor systems that are constitutively desensitized...
September 22, 2016: Journal of Pharmacology and Experimental Therapeutics
Edina Szűcs, Szabolcs Dvorácskó, Csaba Tömböly, Alexandra Büki, Gabriella Kékesi, Gyöngyi Horváth, Sándor Benyhe
Schizophrenia is a serious mental health disorder characterized by several behavioral and biochemicel abnormalities. In a previous study we have shown that mu-opioid (MOP) receptor signaling is impaired in specific brain regions of our three-hit animal model of schizophrenia. Since the cannabinoid system is significantly influenced in schizophrenic patients, in the present work we investigated cannabinoid (CB) receptor binding and G-protein activation in cortical, subcortical and cerebellar regions of control and 'schizophrenic' rats...
October 28, 2016: Neuroscience Letters
Amalia Gastaldelli, Melania Gaggini, Giuseppe Daniele, Demetrio Ciociaro, Eugenio Cersosimo, Devjit Tripathy, Curtis Triplitt, Peter Fox, Nicolas Musi, Ralph DeFronzo, Patricia Iozzo
: GLP-1 receptor agonists (GLP-1-RAs) act on multiple tissues, in addition to the pancreas. Recent studies suggest that GLP-1-RAs act on liver and adipose tissue to reduce insulin resistance (IR). Thus, we evaluated the acute effects of exenatide (EX) on hepatic (Hep-IR) and adipose (Adipo-IR) insulin resistance and glucose uptake. 15 male subjects (age=56±8 y, BMI=29±1 kg/m(2) , A1c=5.7±0.1%) were studied on two occasions, with a double blind subcutaneous injection of exenatide (5 mcg) or placebo (PLC) 30 min before a 75-gram oral glucose tolerance test (OGTT)...
September 17, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jai Shankar K Yadlapalli, Benjamin M Ford, Amit Ketkar, Anqi Wan, Narasimha R Penthala, Robert L Eoff, Paul L Prather, Maxim Dobretsov, Peter A Crooks
: This study determined the antinociceptive effects of morphine and morphine-6-O-sulfate (M6S) in both normal and diabetic rats, and evaluated the comparative role of mu-opioid receptors (mu-ORs) and delta-opioid receptors (delta-ORs) in the antinociceptive action of these opioids. In vitro characterization of mu-OR and delta-OR-mediated signaling by M6S and morphine in stably transfected Chinese hamster ovary (CHO-K1) cells showed that M6S exhibited a 6-fold higher affinity for delta-ORs and modulated G-protein and adenylyl cyclase activity via delta-ORs more potently than morphine...
September 13, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Raehanna J Jamshidi, Laura C Sullivan, Blaine A Jacobs, Teresa A Chavera, Kelly A Berg, William P Clarke
A single administration of the kappa opioid receptor (KOR) antagonist, norbinaltorphimine (norBNI), produces long-term reduction in KOR function in heterologous expression systems and brain that is mediated by activation of c-Jun N-terminal Kinase (JNK). In this study, we examined the long-term effects of norBNI on adult rat peripheral sensory neurons in vivo and ex vivo. Following a single intraplantar ( injection of norBNI into the hindpaw, peripheral KOR-mediated antinociception in the ipsilateral, but not the contralateral, hindpaw was abolished for at least 9 days...
September 7, 2016: Journal of Pharmacology and Experimental Therapeutics
Huiping Ding, Paul W Czoty, Norikazu Kiguchi, Gerta Cami-Kobeci, Devki D Sukhtankar, Michael A Nader, Stephen M Husbands, Mei-Chuan Ko
Despite the critical need, no previous research has substantiated safe opioid analgesics without abuse liability in primates. Recent advances in medicinal chemistry have led to the development of ligands with mixed mu opioid peptide (MOP)/nociceptin-orphanin FQ peptide (NOP) receptor agonist activity to achieve this objective. BU08028 is a novel orvinol analog that displays a similar binding profile to buprenorphine with improved affinity and efficacy at NOP receptors. The aim of this preclinical study was to establish the functional profile of BU08028 in monkeys using clinically used MOP receptor agonists for side-by-side comparisons in various well-honed behavioral and physiological assays...
September 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
Allison Doyle Brackley, Ruben Gomez, Armen N Akopian, Michael A Henry, Nathaniel A Jeske
Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR), those that target the delta class (DOR) also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2) naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy...
September 6, 2016: Cell Reports
András Váradi, Gina F Marrone, Travis C Palmer, Ankita Narayan, Márton R Szabó, Valerie Le Rouzic, Steven G Grinnell, Joan J Subrath, Evelyn Warner, Sanjay Kalra, Amanda Hunkele, Jeremy Pagirsky, Shainnel O Eans, Jessica M Medina, Jin Xu, Ying-Xian Pan, Attila Borics, Gavril W Pasternak, Jay P McLaughlin, Susruta Majumdar
Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism...
September 22, 2016: Journal of Medicinal Chemistry
Gang Chen, Rou-Gang Xie, Yong-Jing Gao, Zhen-Zhong Xu, Lin-Xia Zhao, Sangsu Bang, Temugin Berta, Chul-Kyu Park, Mark Lay, Wei Chen, Ru-Rong Ji
Mechanisms of acute pain transition to chronic pain are not fully understood. Here we demonstrate an active role of β-arrestin 2 (Arrb2) in regulating spinal cord NMDA receptor (NMDAR) function and the duration of pain. Intrathecal injection of the mu-opioid receptor agonist [D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin produces paradoxical behavioural responses: early-phase analgesia and late-phase mechanical allodynia which requires NMDAR; both phases are prolonged in Arrb2 knockout (KO) mice. Spinal administration of NMDA induces GluN2B-dependent mechanical allodynia, which is prolonged in Arrb2-KO mice and conditional KO mice lacking Arrb2 in presynaptic terminals expressing Nav1...
August 19, 2016: Nature Communications
Eva Tudurí, Daniel Beiroa, Johannes Stegbauer, Johan Fernø, Miguel López, Carlos Diéguez, Rubén Nogueiras
Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i...
November 2016: Neuropharmacology
Zhiqiang Yin, Tingting Chai, Pengqian Mu, Nana Xu, Yue Song, Xinlu Wang, Qi Jia, Jing Qiu
This paper presents a multi-residue analytical method for 210 drugs in pork using ultra-high-performance liquid chromatography-Q-Trap tandem mass spectrometry (UPLC-MS/MS) within 20min via positive ESI in scheduled multi-reaction monitoring (MRM) mode. The 210 drugs, belonging to 21 different chemical classes, included macrolides, sulfonamides, tetracyclines, β-lactams, β-agonists, aminoglycosides, antiviral drugs, glycosides, phenothiazine, protein anabolic hormones, non-steroidal anti-inflammatory drugs (NSAIDs), quinolones, antifungal drugs, corticosteroids, imidazoles, piperidines, piperazidines, insecticides, amides, alkaloids and others...
September 9, 2016: Journal of Chromatography. A
Pao-Pao Yang, Geng-Chang Yeh, Teng-Kuang Yeh, Jinghua Xi, Horace H Loh, Ping-Yee Law, Pao-Luh Tao
Oxycodone has been used clinically for over 90 years. While it is known that it exhibits low affinity for the multiple opioid receptors, whether its pharmacological activities are due to oxycodone activation of the opioid receptor type or due to its active metabolite (oxymorphone) that exhibits high affinity for the mu-opioid receptors remains unresolved. Ross and Smith (1997) reported the antinociceptive effects of oxycodone (171nmol, i.c.v.) are induced by putative kappa-opioid receptors in SD rat while others have reported oxycodone activities are due to activation of mu- and/or delta-opioid receptors...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Yuri Kiguchi, Yuri Aono, Yuriko Watanabe, Seiko Yamamoto-Nemoto, Kunihiko Shimizu, Takehiko Shimizu, Yasuhiro Kosuge, John L Waddington, Kumiko Ishige, Yoshihisa Ito, Tadashi Saigusa
Cholinergic neurons in the nucleus accumbens express delta- and mu-opioid receptors that are thought to inhibit neural activity. Delta- and mu-opioid receptors are divided into delta1- and delta2-opioid receptors and mu1- and mu2-opioid receptors, respectively. We analysed the roles of delta- and mu-opioid receptor subtypes in regulating accumbal acetylcholine efflux of freely moving rats using in vivo microdialysis. Other than naloxonazine, given intraperitoneally, delta- and mu-opioid receptor ligands were administered intracerebrally through the dialysis probe...
October 15, 2016: European Journal of Pharmacology
Elyssa B Margolis, Howard L Fields
Increased activity of lateral habenula (LHb) neurons is correlated with aversive states including pain, opioid abstinence, rodent models of depression, and failure to receive a predicted reward. Agonists at the mu opioid receptor (MOR) are among the most powerful rewarding and pain relieving drugs. Injection of the MOR agonist morphine directly into the habenula produces analgesia, raising the possibility that MOR acts locally within the LHb. Consequently, we examined the synaptic actions of MOR agonists in the LHb using whole cell patch clamp recording...
2016: PloS One
Alejandro Vicente-Carrillo, Manuel Álvarez-Rodríguez, Heriberto Rodríguez-Martínez
Endogenous and exogenous opioids modulate reproductive functions in target cells via opioid receptors (μ, δ, and κ). Sperm motility is a metric of gamete functionality, and serves as a suitable parameter for in vitro drug-induced toxicity assays. This study identifies the presence and location of opioid receptors in pig spermatozoa as well as their functional response after in vitro challenge with known agonists (morphine [μ]; [D-Pen 2,5]-enkephanile [δ]; and U 50488 [κ]) and antagonists (naloxone [μ]; naltrindole [δ]; and nor-binaltrorphimine [κ])...
August 2016: Molecular Reproduction and Development
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