A bifunctional nociceptin and mu opioid receptor agonist is analgesic without opioid side effects in nonhuman primates.

Abstract:

:Misuse of prescription opioids, opioid addiction, and overdose underscore the urgent need for developing addiction-free effective medications for treating severe pain. Mu opioid peptide (MOP) receptor agonists provide very effective pain relief. However, severe side effects limit their use in the clinical setting. Agonists of the nociceptin/orphanin FQ peptide (NOP) receptor have been shown to modulate the antinociceptive and reinforcing effects of MOP agonists. We report the discovery and development of a bifunctional NOP/MOP receptor agonist, AT-121, which has partial agonist activity at both NOP and MOP receptors. AT-121 suppressed oxycodone's reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. Our results in nonhuman primates suggest that bifunctional NOP/MOP agonists with the appropriate balance of NOP and MOP agonist activity may provide a dual therapeutic action for safe and effective pain relief and treating prescription opioid abuse.

journal_name

Sci Transl Med

authors

Ding H,Kiguchi N,Yasuda D,Daga PR,Polgar WE,Lu JJ,Czoty PW,Kishioka S,Zaveri NT,Ko MC

doi

10.1126/scitranslmed.aar3483

subject

Has Abstract

pub_date

2018-08-29 00:00:00

issue

456

eissn

1946-6234

issn

1946-6242

pii

10/456/eaar3483

journal_volume

10

pub_type

杂志文章
  • Using health information technology to engage communities in health, education, and research.

    abstract::The August 2011 Clinical and Translational Science Awards conference "Using IT to Improve Community Health: How Health Care Reform Supports Innovation" convened four "Think Tank" sessions. Thirty individuals, representing various perspectives on community engagement, attended the "Health information technology (HIT) a...

    journal_title:Science translational medicine

    pub_type:

    doi:10.1126/scitranslmed.3003363

    authors: Marriott LK,Nelson DA,Allen S,Calhoun K,Eldredge CE,Kimminau KS,Lucero RJ,Pineda-Reyes F,Rumala BB,Varanasi AP,Wasser JS,Shannon J

    更新日期:2012-02-01 00:00:00

  • Stem cells, dot-com.

    abstract::Direct-to-consumer (DTC) advertising of suspect goods and services has burgeoned because of the Internet. Despite very limited approval for use, DTC stem cell-marketed "treatments" have emerged for an array of conditions, creating global public health and safety risks. However, it remains unclear whether such use of s...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3004030

    authors: Liang BA,Mackey TK

    更新日期:2012-09-12 00:00:00

  • Trauma in silico: Individual-specific mathematical models and virtual clinical populations.

    abstract::Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model repro...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa3636

    authors: Brown D,Namas RA,Almahmoud K,Zaaqoq A,Sarkar J,Barclay DA,Yin J,Ghuma A,Abboud A,Constantine G,Nieman G,Zamora R,Chang SC,Billiar TR,Vodovotz Y

    更新日期:2015-04-29 00:00:00

  • A generalized linear-quadratic model for radiosurgery, stereotactic body radiation therapy, and high-dose rate brachytherapy.

    abstract::Conventional radiation therapy for cancer usually consists of multiple treatments (called fractions) with low doses of radiation. These dose schemes are planned with the guidance of the linear-quadratic (LQ) model, which has been the most prevalent model for designing dose schemes in radiation therapy. The high-dose f...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000864

    authors: Wang JZ,Huang Z,Lo SS,Yuh WT,Mayr NA

    更新日期:2010-07-07 00:00:00

  • Nonhuman primates exposed to Zika virus in utero are not protected against reinfection at 1 year postpartum.

    abstract::There is limited information about the impact of Zika virus (ZIKV) exposure in utero on the anti-ZIKV immune responses of offspring. We infected six rhesus macaque dams with ZIKV early or late in pregnancy and studied four of their offspring over the course of a year postpartum. Despite evidence of ZIKV exposure in ut...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaz4997

    authors: Vannella KM,Stein S,Connelly M,Swerczek J,Amaro-Carambot E,Coyle EM,Babyak A,Winkler CW,Saturday G,Gai ND,Hammoud DA,Dowd KA,Valencia LP,Ramos-Benitez MJ,Kindrachuk J,Pierson TC,Peterson KE,Brenchley JM,Whitehead SS,

    更新日期:2020-10-28 00:00:00

  • Gastrointestinal synthetic epithelial linings.

    abstract::Epithelial tissues line the organs of the body, providing an initial protective barrier as well as a surface for nutrient and drug absorption. Here, we identified enzymatic components present in the gastrointestinal epithelium that can serve as selective means for tissue-directed polymerization. We focused on the smal...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.abc0441

    authors: Li J,Wang T,Kirtane AR,Shi Y,Jones A,Moussa Z,Lopes A,Collins J,Tamang SM,Hess K,Shakur R,Karandikar P,Lee JS,Huang HW,Hayward A,Traverso G

    更新日期:2020-08-26 00:00:00

  • Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis.

    abstract::In multiple sclerosis (MS), lymphocyte--in particular B cell--transit between the central nervous system (CNS) and periphery may contribute to the maintenance of active disease. Clonally related B cells exist in the cerebrospinal fluid (CSF) and peripheral blood (PB) of MS patients; however, it remains unclear which s...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3008930

    authors: Palanichamy A,Apeltsin L,Kuo TC,Sirota M,Wang S,Pitts SJ,Sundar PD,Telman D,Zhao LZ,Derstine M,Abounasr A,Hauser SL,von Büdingen HC

    更新日期:2014-08-06 00:00:00

  • Post-anesthesia AMPA receptor potentiation prevents anesthesia-induced learning and synaptic deficits.

    abstract::Accumulating evidence has shown that repeated exposure to general anesthesia during critical stages of brain development results in long-lasting behavioral deficits later in life. To date, there has been no effective treatment to mitigate the neurotoxic effects of anesthesia on brain development. By performing calcium...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaf7151

    authors: Huang L,Cichon J,Ninan I,Yang G

    更新日期:2016-06-22 00:00:00

  • Biotechnology: delivering on the promise.

    abstract::The research and development of innovative new therapies are expensive and risky processes, and companies require substantial resources if they are to translate basic science into modern biomedical products. When resources are limited, as in the current economic climate, biotechnology start-up companies are often amon...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3000357

    authors: Greenwood JC

    更新日期:2010-01-06 00:00:00

  • A vitamin to D-crease sunburn.

    abstract::High doses of oral vitamin D3 attenuate skin inflammation following experimentally induced sun damage. ...

    journal_title:Science translational medicine

    pub_type: 评论,杂志文章

    doi:10.1126/scitranslmed.aan5233

    authors: Scharschmidt TC

    更新日期:2017-06-14 00:00:00

  • A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration.

    abstract::Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non-neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement str...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aao4097

    authors: Kashani AH,Lebkowski JS,Rahhal FM,Avery RL,Salehi-Had H,Dang W,Lin CM,Mitra D,Zhu D,Thomas BB,Hikita ST,Pennington BO,Johnson LV,Clegg DO,Hinton DR,Humayun MS

    更新日期:2018-04-04 00:00:00

  • Impact of guidance documents on translational large animal studies of cartilage repair.

    abstract::Promising therapies for cartilage repair are translated through large animal models toward human application. To guide this work, regulatory agencies publish recommendations ("guidance documents") to direct pivotal large animal studies. These are meant to aid in study design, outline metrics for judging efficacy, and ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aac7019

    authors: Pfeifer CG,Fisher MB,Carey JL,Mauck RL

    更新日期:2015-10-21 00:00:00

  • Striatal dopamine regulates systemic glucose metabolism in humans and mice.

    abstract::The brain is emerging as an important regulator of systemic glucose metabolism. Accumulating data from animal and observational human studies suggest that striatal dopamine signaling plays a role in glucose regulation, but direct evidence in humans is currently lacking. We present a series of experiments supporting th...

    journal_title:Science translational medicine

    pub_type: 杂志文章,随机对照试验

    doi:10.1126/scitranslmed.aar3752

    authors: Ter Horst KW,Lammers NM,Trinko R,Opland DM,Figee M,Ackermans MT,Booij J,van den Munckhof P,Schuurman PR,Fliers E,Denys D,DiLeone RJ,la Fleur SE,Serlie MJ

    更新日期:2018-05-23 00:00:00

  • Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD.

    abstract::Attention deficit hyperactivity disorder (ADHD) is a common and persistent condition characterized by developmentally atypical and impairing inattention, hyperactivity, and impulsiveness. We identified de novo and rare copy number variations (CNVs) in 248 unrelated ADHD patients using million-feature genotyping arrays...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3002464

    authors: Lionel AC,Crosbie J,Barbosa N,Goodale T,Thiruvahindrapuram B,Rickaby J,Gazzellone M,Carson AR,Howe JL,Wang Z,Wei J,Stewart AF,Roberts R,McPherson R,Fiebig A,Franke A,Schreiber S,Zwaigenbaum L,Fernandez BA,Roberts W

    更新日期:2011-08-10 00:00:00

  • Rapid pathogen-specific phenotypic antibiotic susceptibility testing using digital LAMP quantification in clinical samples.

    abstract::Rapid antimicrobial susceptibility testing (AST) is urgently needed for informing treatment decisions and preventing the spread of antimicrobial resistance resulting from the misuse and overuse of antibiotics. To date, no phenotypic AST exists that can be performed within a single patient visit (30 min) directly from ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aal3693

    authors: Schoepp NG,Schlappi TS,Curtis MS,Butkovich SS,Miller S,Humphries RM,Ismagilov RF

    更新日期:2017-10-04 00:00:00

  • Mutational signature of aristolochic acid exposure as revealed by whole-exome sequencing.

    abstract::In humans, exposure to aristolochic acid (AA) is associated with urothelial carcinoma of the upper urinary tract (UTUC). Exome sequencing of UTUCs from 19 individuals with documented exposure to AA revealed a remarkably large number of somatic mutations and an unusual mutational signature attributable to AA. Most of t...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3006200

    authors: Hoang ML,Chen CH,Sidorenko VS,He J,Dickman KG,Yun BH,Moriya M,Niknafs N,Douville C,Karchin R,Turesky RJ,Pu YS,Vogelstein B,Papadopoulos N,Grollman AP,Kinzler KW,Rosenquist TA

    更新日期:2013-08-07 00:00:00

  • Plasmacytoid dendritic cells, interferon signaling, and FcγR contribute to pathogenesis and therapeutic response in childhood immune thrombocytopenia.

    abstract::Immune thrombocytopenia (ITP) is an autoimmune disorder of childhood characterized by immune-mediated destruction of platelets. The mechanisms underlying the pathogenesis of ITP and the therapeutic efficacy of intravenous immunoglobulins (IVIG) in this disorder remain unclear. We show that monocytes from patients with...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3006277

    authors: Sehgal K,Guo X,Koduru S,Shah A,Lin A,Yan X,Dhodapkar KM

    更新日期:2013-07-10 00:00:00

  • Tuberculosis following PD-1 blockade for cancer immunotherapy.

    abstract::Because of the well-established therapeutic benefit of boosting antitumor responses through blockade of the T cell inhibitory receptor PD-1, it has been proposed that PD-1 blockade could also be useful in infectious disease settings, including Mycobacterium tuberculosis (Mtb) infection. However, in preclinical models,...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aat2702

    authors: Barber DL,Sakai S,Kudchadkar RR,Fling SP,Day TA,Vergara JA,Ashkin D,Cheng JH,Lundgren LM,Raabe VN,Kraft CS,Nieva JJ,Cheever MA,Nghiem PT,Sharon E

    更新日期:2019-01-16 00:00:00

  • Translating glutamate: from pathophysiology to treatment.

    abstract::The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, ...

    journal_title:Science translational medicine

    pub_type: 杂志文章,评审

    doi:10.1126/scitranslmed.3002804

    authors: Javitt DC,Schoepp D,Kalivas PW,Volkow ND,Zarate C,Merchant K,Bear MF,Umbricht D,Hajos M,Potter WZ,Lee CM

    更新日期:2011-09-28 00:00:00

  • Interleukin 17 and senescent cells regulate the foreign body response to synthetic material implants in mice and humans.

    abstract::Medical devices and implants made of synthetic materials can induce an immune-mediated process when implanted in the body called the foreign body response, which results in formation of a fibrous capsule around the implant. To explore the immune and stromal connections underpinning the foreign body response, we analyz...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aax3799

    authors: Chung L,Maestas DR Jr,Lebid A,Mageau A,Rosson GD,Wu X,Wolf MT,Tam AJ,Vanderzee I,Wang X,Andorko JI,Zhang H,Narain R,Sadtler K,Fan H,Čiháková D,Le Saux CJ,Housseau F,Pardoll DM,Elisseeff JH

    更新日期:2020-04-15 00:00:00

  • Cancer chemoprevention: Evidence of a nonlinear dose response for the protective effects of resveratrol in humans and mice.

    abstract::Resveratrol is widely promoted as a potential cancer chemopreventive agent, but a lack of information on the optimal dose prohibits rationally designed trials to assess efficacy. To challenge the assumption that "more is better," we compared the pharmacokinetics and activity of a dietary dose with an intake 200 times ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa7619

    authors: Cai H,Scott E,Kholghi A,Andreadi C,Rufini A,Karmokar A,Britton RG,Horner-Glister E,Greaves P,Jawad D,James M,Howells L,Ognibene T,Malfatti M,Goldring C,Kitteringham N,Walsh J,Viskaduraki M,West K,Miller A,Hemingwa

    更新日期:2015-07-29 00:00:00

  • Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model.

    abstract::Down syndrome (DS) is among the most frequent genetic causes of intellectual disability, and ameliorating this deficit is a major goal in support of people with trisomy 21. The Ts65Dn mouse recapitulates some major brain structural and behavioral phenotypes of DS, including reduced size and cellularity of the cerebell...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3005983

    authors: Das I,Park JM,Shin JH,Jeon SK,Lorenzi H,Linden DJ,Worley PF,Reeves RH

    更新日期:2013-09-04 00:00:00

  • Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer's disease pathology.

    abstract::Aggregation of β-amyloid (Aβ) in the brain begins to occur years before the clinical onset of Alzheimer's disease (AD). Before Aβ aggregation, concentrations of extracellular soluble Aβ in the interstitial fluid (ISF) space of the brain, which are regulated by neuronal activity and the sleep-wake cycle, correlate with...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3004291

    authors: Roh JH,Huang Y,Bero AW,Kasten T,Stewart FR,Bateman RJ,Holtzman DM

    更新日期:2012-09-05 00:00:00

  • Therapy with CTLA4-Ig and an antiviral monoclonal antibody controls chikungunya virus arthritis.

    abstract::In 2013, chikungunya virus (CHIKV) transmission was documented in the Western Hemisphere, and the virus has since spread throughout the Americas with more than 1.8 million people infected in more than 40 countries. CHIKV targets the joints, resulting in symmetric polyarthritis that clinically mimics rheumatoid arthrit...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aah3438

    authors: Miner JJ,Cook LE,Hong JP,Smith AM,Richner JM,Shimak RM,Young AR,Monte K,Poddar S,Crowe JE Jr,Lenschow DJ,Diamond MS

    更新日期:2017-02-01 00:00:00

  • Effect of bipolar androgen therapy for asymptomatic men with castration-resistant prostate cancer: results from a pilot clinical study.

    abstract::Targeting androgen receptor (AR) axis signaling by disrupting androgen-AR interactions remains the primary treatment for metastatic prostate cancer. Unfortunately, all men develop resistance to primary castrating therapy and secondary androgen deprivation therapies (ADTs). Resistance develops in part because castratio...

    journal_title:Science translational medicine

    pub_type: 临床试验,杂志文章

    doi:10.1126/scitranslmed.3010563

    authors: Schweizer MT,Antonarakis ES,Wang H,Ajiboye AS,Spitz A,Cao H,Luo J,Haffner MC,Yegnasubramanian S,Carducci MA,Eisenberger MA,Isaacs JT,Denmeade SR

    更新日期:2015-01-07 00:00:00

  • IVIG-mediated protection against necrotizing pneumonia caused by MRSA.

    abstract::New therapeutic approaches are urgently needed to improve survival outcomes for patients with necrotizing pneumonia caused by Staphylococcus aureus One such approach is adjunctive treatment with intravenous immunoglobulin (IVIG), but clinical practice guidelines offer conflicting recommendations. In a preclinical rabb...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aag1153

    authors: Diep BA,Le VT,Badiou C,Le HN,Pinheiro MG,Duong AH,Wang X,Dip EC,Aguiar-Alves F,Basuino L,Marbach H,Mai TT,Sarda MN,Kajikawa O,Matute-Bello G,Tkaczyk C,Rasigade JP,Sellman BR,Chambers HF,Lina G

    更新日期:2016-09-21 00:00:00

  • Altered placebo and drug labeling changes the outcome of episodic migraine attacks.

    abstract::Information provided to patients is thought to influence placebo and drug effects. In a prospective, within-subjects, repeated-measures study of 66 subjects with episodic migraine, we investigated how variations in medication labeling modified placebo and drug effects. An initial attack with no treatment served as a c...

    journal_title:Science translational medicine

    pub_type: 杂志文章,随机对照试验

    doi:10.1126/scitranslmed.3006175

    authors: Kam-Hansen S,Jakubowski M,Kelley JM,Kirsch I,Hoaglin DC,Kaptchuk TJ,Burstein R

    更新日期:2014-01-08 00:00:00

  • Local iontophoretic administration of cytotoxic therapies to solid tumors.

    abstract::Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents whil...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.3009951

    authors: Byrne JD,Jajja MR,O'Neill AT,Bickford LR,Keeler AW,Hyder N,Wagner K,Deal A,Little RE,Moffitt RA,Stack C,Nelson M,Brooks CR,Lee W,Luft JC,Napier ME,Darr D,Anders CK,Stack R,Tepper JE,Wang AZ,Zamboni WC,Yeh JJ,

    更新日期:2015-02-04 00:00:00

  • STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade.

    abstract::Stimulator of interferon genes (STING) is a cytosolic receptor that senses both exogenous and endogenous cytosolic cyclic dinucleotides (CDNs), activating TBK1/IRF3 (interferon regulatory factor 3), NF-κB (nuclear factor κB), and STAT6 (signal transducer and activator of transcription 6) signaling pathways to induce r...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aaa4306

    authors: Fu J,Kanne DB,Leong M,Glickman LH,McWhirter SM,Lemmens E,Mechette K,Leong JJ,Lauer P,Liu W,Sivick KE,Zeng Q,Soares KC,Zheng L,Portnoy DA,Woodward JJ,Pardoll DM,Dubensky TW Jr,Kim Y

    更新日期:2015-04-15 00:00:00

  • The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy.

    abstract::Patients undergoing surgical resection of primary breast tumors confront a risk for metastatic recurrence that peaks sharply 12 to 18 months after surgery. The cause of early metastatic relapse in breast cancer has long been debated, with many ascribing these relapses to the natural progression of the disease. Others ...

    journal_title:Science translational medicine

    pub_type: 杂志文章

    doi:10.1126/scitranslmed.aan3464

    authors: Krall JA,Reinhardt F,Mercury OA,Pattabiraman DR,Brooks MW,Dougan M,Lambert AW,Bierie B,Ploegh HL,Dougan SK,Weinberg RA

    更新日期:2018-04-11 00:00:00