318 results on '"Lambert DG"'
Search Results
2. [Dmt1]N/OFQ(1–13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist
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Molinari, S, Camarda, V, Rizzi, A, Marzola, G, Salvadori, S, Marzola, E, Molinari, P, McDonald, J, Ko, MC, Lambert, DG, Caloʼ, G, and Guerrini, R
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- 2013
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3. Opioid receptors
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McDonald, John and Lambert, DG
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- 2005
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4. Relationships Between Outdoor Time, Physical Activity, Sedentary Time, and Body Mass Index in Children: A 12-Country Study
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Larouche, R, Mire, Ef, Belanger, K, Barreira, Tv, Chaput, Jp, Fogelholm, M, Hu, G, Lambert, Ev, Maher, C, Maia, J, Olds, T, Onywera, V, Sarmiento, Ol, Standage, M, Tudor-Locke, C, Katzmarzyk, Pt, Tremblay, Ms, Church, Ts, Lambert, Dg, Barreira, T, Broyles, S, Butitta, B, Champagne, C, Cocreham, S, Dentro, K, Drazba, K, Harrington, D, Johnson, W, Milauskas, D, Mire, E, Tohme, A, Rodarte, R, Amoroso, B, Luopa, J, Neiberg, R, Rushing, S, Lewis, L, Ferrar, K, Georgiadis, E, Stanley, R, Matsudo, Vkr, Matsudo, S, Araujo, T, de Oliveira LC, Rezende, L, Fabiano, L, Bezerra, D, Ferrari, G, Belanger, P, Borghese, M, Boyer, C, Leblanc, A, Francis, C, Leduc, G, Zhao, P, Diao, Cm, Li, W, Li WQ Liu, Liu, Eq, GS Liu HY, Ma, J, Qiao, Yj, Tian, Hg, Wang, Y, Zhang, T, Zhang, Fx, Sarmiento, O, Acosta, J, Alvira, Y, Diaz, Mp, Gamez, R, Garcia, Mp, Gomez, Lg, Gonzalez, L, Gonzalez, S, Grijalba, C, Gutierrez, L, Leal, D, Lemus, N, Mahecha, E, Mahecha, Mp, Mahecha, R, Ramirez, A, Rios, P, Suarez, A, Triana, C, Hovi, E, Kivela, J, Rasanen, S, Sanna, Roito, Taru, Saloheimo, Valta, L, Kurpad, A, Kuriyan, R, Lokesh, Dp, D'Almeida, Ms, Mattilda, Ra, Correa, L, Vijay, D, Wachira, Lj, Muthuri, S, Borges, Ad, Cachada, Sos, de Chaves RN, Gomes, Tnqf, Pereira, Sis, Santos, Dmde, dos Santos FK, da Silva PGR, de Souza MC, Lambert, V, April, M, Uys, M, Naidoo, N, Synyanya, N, Carstens, M, Cumming, S, Drenowatz, C, Emm, L, Gillison, F, Zakrzewski, J, Braud, A, Donatto, S, Lemon, C, Jackson, A, Pearson, A, Pennington, G, Ragus, D, Roubion, R, Schuna, J, Wiltz, D, Batterham, A, Kerr, J, Pratt, M, Pietrobelli, A, Larouche, Richard, Barreira, Tiago V., Hu, Gang, Maia, José, Sarmiento, Olga L., Katzmarzyk, Peter T., Mire, Emily F., Chaput, Jean Philippe, Lambert, Estelle V., Olds, Tim, Standage, Martyn, Belanger, Kevin, Fogelholm, Mikael, Maher, Carol, Onywera, Vincent, Tudor-Locke, Catrine, Tremblay, Mark S., and ISCOLE Research Group
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Male ,medicine.medical_specialty ,Pediatric Obesity ,Time Factors ,Sports medicine ,Cross-sectional study ,health promotion ,RJ101 ,Health Behavior ,Physical activity ,Physical Therapy, Sports Therapy and Rehabilitation ,Standard score ,RA773 ,Body Mass Index ,RC1200 ,03 medical and health sciences ,0302 clinical medicine ,Residence Characteristics ,Surveys and Questionnaires ,Accelerometry ,medicine ,Humans ,Orthopedics and Sports Medicine ,030212 general & internal medicine ,Child ,2. Zero hunger ,Sedentary time ,exercise ,030229 sport sciences ,medicine.disease ,motor behavior ,Obesity ,Country study ,Cross-Sectional Studies ,Social Class ,Pediatrics, Perinatology and Child Health ,epidemiology ,Female ,Sedentary Behavior ,Psychology ,Body mass index ,Demography - Abstract
Purpose: This study investigated the relationship between outdoor time and physical activity (PA), sedentary time (SED), and body mass index z scores among children from 12 lower-middle-income, upper-middle-income, and high-income countries. Methods: In total, 6478 children (54.4% girls) aged 9–11 years participated. Outdoor time was self-reported, PA and SED were assessed with ActiGraph GT3X+ accelerometers, and height and weight were measured. Data on parental education, neighborhood collective efficacy, and accessibility to neighborhood recreation facilities were collected from parent questionnaires. Country latitude and climate statistics were collected through national weather data sources. Gender-stratified multilevel models with parental education, climate, and neighborhood variables as covariates were used to examine the relationship between outdoor time, accelerometry measures, and body mass index z scores. Results: Each additional hour per day spent outdoors was associated with higher moderate- to vigorous-intensity PA (boys: +2.8 min/d; girls: +1.4 min/d), higher light-intensity PA (boys: +2.0 min/d; girls: +2.3 min/d), and lower SED (boys: −6.3 min/d; girls: −5.1 min/d). Effect sizes were generally weaker in lower-middle-income countries. Outdoor time was not associated with body mass index z scores. Conclusions: Outdoor time was associated with higher PA and lower SED independent of climate, parental education, and neighborhood variables, but effect sizes were small. However, more research is needed in low- and middle-income countries.
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- 2019
5. Drugs and receptors
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Lambert, DG
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- 2004
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6. Opioid receptors
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McDonald, J, primary and Lambert, DG, additional
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- 2014
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7. Pharmacological characterization of the nociceptin / orphanin FQ receptor antagonist SB-612111: in vitro studies
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Spagnolo, Barbara, Carra', Giacomo, Fantin, Martina, Fischetti, Carmela, Hebbes, C, Mcdonald, J, Barnes, Ta, Rizzi, Anna, Trapella, Claudio, Fanton, Giulia, Morari, Michele, Lambert, Dg, Regoli, Domenico, and Calo', Girolamo
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- 2007
8. In vitro and in vivo pharmacological characterization of the novel UT receptor ligand [Pen(5), DTrp(7), Dab(8)] urotensin II(4-11) (UFP-803)
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Camarda, Valeria, Spagnol, Martina, Song, W, Vergura, Raffaella, Roth, Al, Thompson, Jp, Rowbotham, Dj, Guerrini, Remo, Marzola, Erika, Salvadori, Severo, Cavanni, P, Regoli, Domenico, Douglas, Sa, Lambert, Dg, and Calo', Girolamo
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[Ca ,Urotensin-II ,2+ ,Rat aorta ,UFP-803 ,] ,i ,Mouse plasma extravasation ,Urantide ,UT receptor - Published
- 2006
9. Pharmacological profiles of presynaptic nociceptin/orphanin FQ receptors modulating 5-hydroxytryptamine and noradrenaline release in the rat neocortex
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Marti, M, Stocchi, S, Paganini, F, Mela, F, DE RISI, C, Calo', G, Guerrini, R, Barnes, Ta, Lambert, Dg, Beani, L, Bianchi, C, and Morari, M
- Published
- 2003
10. UFP-101, a high affinity antagonist for the nociceptin/orphanin FQ receptor: radioligand and GTPgamma35S binding studies
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Mcdonald, J, Calo', G, Guerrini, R, and Lambert, Dg
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- 2003
11. Effects of [(pF)Phe4]nociceptin/orphanin FQ(1-13)NH2 on GTPgamma35S binding and cAMP formation in chinese hamster ovary cells expressing the human nociceptin/orphanin FQ receptor
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Mcdonald, J, Barnes, Ta, Calo', G, Guerrini, R, Rowbotham, Dj, and Lambert, Dg
- Published
- 2002
12. Effects of nociceptin and endomorphin 1 on the electrically stimulated human vas deferens
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Bigoni, R, Calo', G, Guerrini, R, STRUPISH JW ROWBOTHAM DJ, and Lambert, Dg
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- 2001
13. Characterization and comparison of novel ligands for the nociceptin/orphanin FQ receptor
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Hashiba, E, Harrison, C, Calo', G, Guerrini, R, Rowbotham, Dj, Smith, G, and Lambert, Dg
- Published
- 2001
14. Antagonistic effects of [Nphe1]nociceptin(1-13)NH2 on nociceptin receptor mediated inhibition of cAMP formation in Chinese ovary cells stably expressing the recombinant human nociceptin receptor
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Hashimoto, Y, Calo', Girolamo, Guerrini, R, Smith, G, and Lambert, Dg
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- 2000
15. In vitro characterization of J-113397 a non peptide nociceptin/orphanin FQ receptor antagonist, N S Arch Pharmacol 361, 565-568
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Bigoni, R, Calo', G, Rizzi, A, Guerrini, R, DE RISI, C, Hashimoto, Y, Hashiba, E, Lambert, Dg, and Regoli, D
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- 2000
16. Comparison of the effects of [Phe(1)Psi(CH2-NH)Gly(2)]nociceptin (1-13)NH2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors
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Okawa, H, Nicol, B, Bigoni, R, Hirst, Ra, Calo, G, Guerrini, R., Rowbotham, Dj, Smart, D, Mcknight, At, and Lambert, Dg
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Binding ,Cyclic AMP ,Glutamate release ,Nociceptin receptor ,Nociceptin/orphanin FQ ,Rat ,Vas deferens - Published
- 1999
17. (1999). Comparison of the effects of [Phe1psi(CH2-NH)Gly2]Nociceptin (1-13)NH2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors
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Okawa, H, Nicol, B, Bigoni, R, Hirst, Ra, Calo', G, Guerrini, R, Rowbotham, Dj, Smart, D, Mcknight, At, and Lambert, Dg
- Published
- 1999
18. [Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist
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Molinari, S, primary, Camarda, V, additional, Rizzi, A, additional, Marzola, G, additional, Salvadori, S, additional, Marzola, E, additional, Molinari, P, additional, McDonald, J, additional, Ko, MC, additional, Lambert, DG, additional, Calo', G, additional, and Guerrini, R, additional
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- 2012
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19. [Dmt1]N/OFQ(1-13)-NH2: a potent nociceptin/orphanin FQ and opioid receptor universal agonist.
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Molinari, S, Camarda, V, Rizzi, A, Marzola, G, Salvadori, S, Marzola, E, Molinari, P, McDonald, J, Ko, MC, Lambert, DG, Calo', G, and Guerrini, R
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NOCICEPTIN ,DRUG synergism ,DRUG administration ,ANALGESICS ,OPIOID receptors ,PHARMACOLOGY ,GENE expression ,LABORATORY rodents - Abstract
Background and Purpose Intrathecally (i.t.) administered nociceptin/orphanin FQ ( N/OFQ) evokes antinociceptive effects in rodents. Recent studies in monkeys demonstrated that i.t. co-application of N/OFQ and morphine elicits synergistic antinociceptive actions suggesting mixed N/OFQ peptide ( NOP) and μ opioid receptor agonists as innovative spinal analgesics. Thus, novel N/OFQ related peptides were synthesized in order to identify and pharmacologically characterize a mixed NOP/ μ opioid receptor agonist. Experimental Approach The following in vitro assays were used: calcium mobilization in cells expressing the human NOP or classical opioid receptors and chimeric G proteins, receptor and [
35 S]-GTPγS binding, [35 S]-GTPγS binding in rat spinal cord membranes, guinea pig ileum bioassay. In vivo experiments were performed in monkeys using the tail withdrawal assay. Key Results From calcium mobilization studies [Dmt1 ]N/OFQ(1-13)-NH2 was selected as the most potent and least selective compound. The mixed NOP/opioid full agonist activity and high affinity of [Dmt1 ]N/OFQ(1-13)-NH2 was confirmed at human recombinant receptors in receptor binding, calcium mobilization and/or [35 S]-GTPγS binding studies, at rat spinal cord receptors in [35 S]-GTPγS binding experiments, and at guinea pig receptors inhibiting neurogenic contractions in the ileum. In vivo in the tail withdrawal assay in monkeys i.t. [Dmt1 ]N/OFQ(1-13)-NH2 was able to elicit robust and long-lasting antinociceptive effects. Conclusions and Implications Collectively, these results demonstrate that [Dmt1 ]N/OFQ(1-13)-NH2 behaves as NOP/opioid receptor universal agonist and substantiate the suggestion that such mixed ligands are worthy of development as innovative spinal analgesics. [ABSTRACT FROM AUTHOR]- Published
- 2013
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20. Carbachol-stimulated calcium entry in SH-SY5Y human neuroblastoma cells: Which route?
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Lambert, DG, primary and Nahorski, SR, additional
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- 1992
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21. Pain medicine: advances in basic sciences and clinical practice.
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Colvin LA, Lambert DG, Colvin, L A, and Lambert, D G
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- 2008
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22. Short communication. Neither nociceptin nor its receptor are present in human synovial fluid or tissue
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Kumar, N, Smart, D, Mason, S, McKnight, AT, Rowbotham, DJ, and Lambert, DG
- Abstract
Our aim was to identify the nociceptin receptor and its endogenous ligand, nociceptin, in human peripheral tissue. Synovial tissue was obtained from 11 patients (ASA I-III, 66-84 yr) undergoing elective total knee replacement. Synovial fluid was obtained from another 10 patients (ASA I-III, 57-81 yr). Fluid was mixed with trifluoracetic acid and the tissue with isopentone before freezing at -70°C. Nociceptin receptor identification was performed using a [3H]nociceptin binding assay and nociceptin detection by radioimmunoassay. There was no specific [3H]nociceptin binding to knee synovial tissue and radioimmunoassay did not detect nociceptin. Neither the nociceptin receptor nor nociceptin was found in human synovial tissue or fluid.
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- 1999
23. Analgesia induced by metoclopramide
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Appadu, BL and Lambert, DG
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- 1993
24. Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505).
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Dietis N, McDonald J, Molinari S, Calo G, Guerrini R, Rowbotham DJ, Lambert DG, Dietis, N, McDonald, J, Molinari, S, Calo, G, Guerrini, R, Rowbotham, D J, and Lambert, D G
- Abstract
Background: While producing good-quality analgesia, µ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of δ-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505).Methods: We measured receptor binding affinity in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, k-opioid (KOP), nociceptin/orphanin (NOP) receptors. For activation, we measured the binding of GTPγ(35)S to membranes from CHO(hMOP), CHO(hDOP), rat cerebrocortex, and rat spinal cord. In addition, we assessed 'end organ' responses in the guinea pig ileum and mouse vas deferens.Results: UFP-505 bound to CHO(hMOP) and CHO(hDOP) with (binding affinity) pK(i) values of 7.79 and 9.82, respectively. There was a weak interaction at KOP and NOP (pK(i) 6.29 and 5.86). At CHO(hMOP), UFP-505 stimulated GTPγ(35)S binding with potency (pEC(50)) of 6.37 and in CHO(hDOP) reversed the effects of a DOP agonist with affinity (pK(b)) of 9.81 (in agreement with pK(i) at DOP). UFP-505 also stimulated GTPγ(35)S binding in rat cerebrocortex and spinal cord with pEC(50) values of 6.11-6.53. In the guinea pig ileum (MOP-rich preparation), UFP-505 inhibited contractility with pEC(50) of 7.50 and in the vas deferens (DOP-rich preparation) reversed the effects of a DOP agonist with an affinity (pA(2)) of 9.15.Conclusions: We have shown in a range of preparations and assays that UFP-505 behaves as a potent MOP agonist and DOP antagonist; a MOP/DOP bifunctional opioid. Further studies in dual expression systems and whole animals with this prototype are warranted. [ABSTRACT FROM AUTHOR]- Published
- 2012
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25. Assessment of nociceptin/orphanin FQ and micro-opioid receptor mRNA in the human right atrium.
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McDonald J, Leonard AD, Serrano-Gomez A, Young SP, Swanevelder J, Thompson JP, Lambert DG, McDonald, J, Leonard, A D, Serrano-Gomez, A, Young, S P, Swanevelder, J, Thompson, J P, and Lambert, D G
- Abstract
Background: The expression of micro (mu: MOP) and nociceptin/orphanin FQ (NOP) receptors in the human myocardium is controversial. In this polymerase chain reaction (PCR)-based study using human right atrial biopsies, we have (i) probed for mRNA encoding NOP receptor and its endogenous peptide precursor, ppN/OFQ, and mRNA encoding MOP and (ii) attempted to correlate expression with cardiac function.Methods: mRNA encoding MOP, NOP, and the precursor for NOP (ppN/OFQ) was assessed by quantitative real-time PCR (Q-PCR) using validated TaqMan primers and compared with a housekeeper (glyceraldehyde-3-phosphate dehydrogenase, GAPDH). Q-PCR data are expressed as the difference in cycle threshold (DeltaC(t)=C(tGene of interest)-C(tGAPDH): high value, low expression) and patients were grouped according to left ventricular ejection fraction (LVEF).Results: Forty patients were recruited; NOP, MOP, and ppN/OFQ mRNA were measured in 38, 29, and 10 patients, respectively. DeltaC(t) (median and range) values for NOP and MOP were 10.9 (7.8-13.7) and 16.0 (12.3-18.9), respectively, representing low expression of MOP and approximately 34-fold more NOP. MOP mRNA was not detected in seven samples and with DeltaC(t) values of approximately 20, ppN/OFQ was considered absent. When patients were grouped into normal (>50%) and impaired (<50%) LVEF, there was no difference between the groups for either NOP or MOP. In some patients, intraoperative LVEF was estimated using transoesophageal echocardiography, and there was no correlation with either NOP or MOP.Conclusions: The human right atrium of patients with coronary artery disease and heart failure expresses mRNA encoding NOP and possibly low levels of MOP. This does not correlate with degree of cardiac dysfunction. In addition, the atrium does not express ppN/OFQ mRNA. [ABSTRACT FROM AUTHOR]- Published
- 2010
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26. Nociceptin/orphanin FQ (N/OFQ) modulates immunopathology and airway hyperresponsiveness representing a novel target for the treatment of asthma
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Singh S. R., Sullo N., Matteis M., Spaziano G., McDonald J., Saunders R., Woodman L., Urbanek K., De Angelis A., De Palma R., Berair R., Pancholi M., Mistry V., Rossi F., Guerrini R., Calo G., D'Agostino B., Brightling C. E., Lambert D. G., Singh, Shailendra R, Sullo, Nikol, Matteis, Maria, Spaziano, Giuseppe, Mcdonald, John, Saunders, Ruth, Woodman, Lucy, Urbanek, Konrad, DE ANGELIS, Antonella, DE PALMA, Raffaele, Berair, Rachid, Pancholi, Mitesh, Mistry, Vijay, Rossi, Francesco, Guerrini, Remo, Calò, Girolamo, D'Agostino, Bruno, Brightling, Christopher E, Lambert, David G., Singh, Sr, Sullo, N, Matteis, M, Spaziano, G, Mcdonald, J, Saunders, R, Woodman, L, Urbanek, K, De Angelis, A, De Palma, R, Berair, R, Pancholi, M, Mistry, V, Rossi, F, Guerrini, R, Calò, G, D'Agostino, B, Brightling, Ce, Lambert, Dg, Singh, S. R., Sullo, N., Matteis, M., Spaziano, G., Mcdonald, J., Saunders, R., Woodman, L., Urbanek, K., De Angelis, A., De Palma, R., Berair, R., Pancholi, M., Mistry, V., Rossi, F., Guerrini, R., Calo, G., D'Agostino, B., Brightling, C. E., and Lambert, D. G.
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Male ,asthma ,bronchoconstriction ,chemotaxis ,eosinophils ,immunomodulation ,inflammation ,mast cells ,nociceptin/orphanin FQ ,ova-sensitization ,wound healing ,Socio-culturale ,Nociceptin Receptor ,Mice ,Nociceptin/orphanin FQ (N/OFQ) ,Respiratory Hypersensitivity ,Animals ,Humans ,eosinophil ,Cells, Cultured ,Pharmacology ,Mice, Inbred BALB C ,Middle Aged ,respiratory system ,Research Papers ,Asthma ,respiratory tract diseases ,Opioid Peptides ,Receptors, Opioid ,Female ,chemotaxi ,mast cell - Abstract
BACKGROUND AND PURPOSE: There is evidence supporting a role for the nociceptin/orphanin FQ (N/OFQ; NOP) receptor and its endogenous ligand N/OFQ in the modulation of neurogenic inflammation, airway tone and calibre. We hypothesized that NOP receptor activation has beneficial effects upon asthma immunopathology and airway hyperresponsiveness. Therefore, the expression and function of N/OFQ and the NOP receptor were examined in healthy and asthmatic human airway tissues. The concept was further addressed in an animal model of allergic asthma. EXPERIMENTAL APPROACH: NOP receptor expression was investigated by quantitative real-time PCR. Sputum N/OFQ was determined by RIA. N/OFQ function was tested using several assays including proliferation, migration, collagen gel contraction and wound healing. The effects of N/OFQ administration in vivo were studied in ovalbumin (OVA)-sensitized and challenged mice. KEY RESULTS: NOP receptors were expressed on a wide range of human and mouse immune and airway cells. Eosinophils expressed N/OFQ-precursor mRNA and their number correlated with N/OFQ concentration. N/OFQ was found in human sputum and increased in asthma. Additionally, in asthmatic human lungs N/OFQ immunoreactivity was elevated. NOP receptor activation inhibited migration of immunocytes and increased wound healing in airway structural cells. Furthermore, N/OFQ relaxed spasmogen-stimulated gel contraction. Remarkably, these findings were mirrored in OVA-mice where N/OFQ treatment before or during sensitization substantially reduced airway constriction and immunocyte trafficking to the lung, in particular eosinophils. N/OFQ also reduced inflammatory mediators and mucin production. CONCLUSIONS AND IMPLICATIONS: We demonstrated a novel dual airway immunomodulator/bronchodilator role for N/OFQ and suggest targeting this system as an innovative treatment for asthma.
- Published
- 2016
27. Danavorexton (TAK-925): an orexin receptor 2 agonist as a new 'arousal' agent.
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Lambert DG and Hirota K
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- Animals, Orexin Receptors, Orexins, Analgesics, Opioid pharmacology, Arousal, Piperidines, Sulfonamides
- Abstract
A preclinical study in animals has further characterised a new 'arousal' agent. Danavorexton (TAK-925) is an agonist for orexin receptor 2 where it promotes recovery from inhalational and i.v. anaesthesia and opioid sedation. Although danavorexton reverses opioid sedation, it does not compromise analgesia. This could be a useful addition to the postoperative drug cupboard., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)
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- 2024
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28. In vitro sepsis up-regulates Nociceptin/Orphanin FQ receptor expression and function on human T- but not B-cells.
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Bird MF, Hebbes CP, Tamang A, Willets JM, Thompson JP, Guerrini R, Calo G, and Lambert DG
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- Animals, Humans, Nociceptin Receptor, Granulocyte-Macrophage Colony-Stimulating Factor, Lipopolysaccharides pharmacology, Interleukin-4, Interleukin-6, Opioid Peptides physiology, Nociceptin, Receptors, Opioid metabolism, Sepsis drug therapy
- Abstract
Background and Purpose: In animal models of sepsis, increased activation of the Nociceptin/Orphanin FQ (N/OFQ) receptor NOP is associated with mortality and NOP antagonists improved survival. We have explored the role of the N/OFQ-NOP system in freshly isolated volunteer human B- and T-cells incubated with lipopolysaccharide (LPS) and peptidoglycan G (PepG) as a model of in vitro sepsis., Experimental Approach: B- and T-cell NOP expression was measured using the NOP fluorescent probe N/OFQ
ATTO594 , N/OFQ content was measured using immunofluorescence, N/OFQ release was tracked using a CHOhNOPGαiq5 biosensor assay and NOP function was measured using transwell migration and cytokine/chemokine release using a 25-plex assay format. Cells were challenged with LPS/PepG., Key Results: CD19-positive B-cells bound N/OFQATTO594 ; they also contain N/OFQ. Stimulation with CXCL13/IL-4 increased N/OFQ release. N/OFQ trended to reduced migration to CXCL13/IL-4. Surface NOP expression was unaffected by LPS/PepG, but this treatment increased GM-CSF release in an N/OFQ sensitive manner. CD3-positive T-cells did not bind N/OFQATTO594 ; they did contain N/OFQ. Stimulation with CXCL12/IL-6 increased N/OFQ release. When incubated with LPS/PepG, NOP surface expression was induced leading to N/OFQATTO594 binding. In LPS/PepG-treated cells, N/OFQ reduced migration to CXCL12/IL-6. LPS/PepG increased GM-CSF release in an N/OFQ sensitive manner., Conclusions and Implications: We suggest both a constitutive and sepsis-inducible N/OFQ-NOP receptor autocrine regulation of B- and T-cell function, respectively. These NOP receptors variably inhibit migration and reduce GM-CSF release. These data provide mechanistic insights to the detrimental role for increased N/OFQ signalling in sepsis and suggest a potential role for NOP antagonists as treatments., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)- Published
- 2023
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29. Soluble Vascular Adhesion Protein 1 (sVAP-1) as a biomarker for pregnancy complications: A pilot study.
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Danielli M, Thomas RC, Gillies CL, Lambert DG, Khunti K, and Tan BK
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- Female, Humans, Pregnancy, Biomarkers, Pilot Projects, Retrospective Studies, Vascular Cell Adhesion Molecule-1, Cell Adhesion Molecules metabolism, Pregnancy Complications
- Abstract
Background: Vascular adhesion protein 1 (VAP-1) has been implicated in a wide range of clinical conditions. Moreover, serum levels are associated with disease prediction and progression in several clinical studies. There is a paucity of data on VAP-1 and pregnancy. Given the emerging role of VAP-1 in pregnancy, the aim of this study was to examine sVAP-1 as an early biomarker of pregnancy complications, especially hypertension during pregnancy. The objectives of the study are to associate sVAP-1 levels with other pregnancy complications, patient demographics and blood tests performed throughout pregnancy., Methods: We conducted a pilot study in a cohort of pregnant women (gestational week lower than 20 at the time of recruitment) attending their first antenatal ultrasound scan at the Leicester Royal Infirmary (LRI, UK). Data were both prospectively generated (from blood sample analysis) and retrospectively collected (from hospital records)., Results: From July and October 2021, a total of 91 participants were enrolled. Using ELISA (enzyme-linked immunosorbent assay), we found reduced serum levels of sVAP-1 in pregnant women with either pregnancy induced hypertension (PIH) (310 ng/mL) or GDM (366.73 ng/mL) as compared to controls (427.44 ng/mL and 428.34 ng/mL, respectively). No significant difference was found between women with FGR compared to controls (424.32 ng/mL vs 424.52 ng/mL), and patients with any pregnancy complications compared to healthy pregnancies (421.28 ng/mL vs 428.34 ng/mL)., Conclusion: Further studies are needed to establish whether or not sVAP-1 might be considered as an early, non-invasive, and affordable biomarker to screen women who will develop PIH or GDM. Our data will aid sample size calculations for such larger studies., Competing Interests: DGL is a scientific adviser to Cellomatics, a SME-CRO. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The remaining authors declare no conflict of interest., (Copyright: © 2023 Danielli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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30. Opioids and opioid receptors; understanding pharmacological mechanisms as a key to therapeutic advances and mitigation of the misuse crisis.
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Lambert DG
- Abstract
Opioids are a mainstay in acute pain management and produce their effects and side effects (e.g., tolerance, opioid-use disorder and immune suppression) by interaction with opioid receptors. I will discuss opioid pharmacology in some controversial areas of enquiry of anaesthetic relevance. The main opioid target is the µ (mu,MOP) receptor but other members of the opioid receptor family, δ (delta; DOP) and κ (kappa; KOP) opioid receptors also produce analgesic actions. These are naloxone-sensitive. There is important clinical development relating to the Nociceptin/Orphanin FQ (NOP) receptor, an opioid receptor that is not naloxone-sensitive. Better understanding of the drivers for opioid effects and side effects may facilitate separation of side effects and production of safer drugs. Opioids bind to the receptor orthosteric site to produce their effects and can engage monomer or homo-, heterodimer receptors. Some ligands can drive one intracellular pathway over another. This is the basis of biased agonism (or functional selectivity). Opioid actions at the orthosteric site can be modulated allosterically and positive allosteric modulators that enhance opioid action are in development. As well as targeting ligand-receptor interaction and transduction, modulating receptor expression and hence function is also tractable. There is evidence for epigenetic associations with different types of pain and also substance misuse. As long as the opioid narrative is defined by the 'opioid crisis' the drive to remove them could gather pace. This will deny use where they are effective, and access to morphine for pain relief in low income countries., Competing Interests: DGL is Chief Scientific Officer at Cellomatics, a SME-CRO and chairs the Board of British Journal of Anaesthesia., (© 2023 The Author.)
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- 2023
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31. British Journal of Anaesthesia: a leading publication and a registered charity.
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Lambert DG, Struys MMRF, and Howell S
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- Humans, Publishing, Charities, Anesthesiology, Anesthesia, Biomedical Research
- Abstract
The British Journal of Anaesthesia organisation is a registered charity comprised of two interlinked missions: provision of impactful publications and funding the generation and dissemination of research to the wider anaesthetic community. This centenary editorial highlights our charitable activity that covers funding of research infrastructure, meeting support and funding of a diverse portfolio of international research grants., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)
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- 2023
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32. Celebrating the first centenary of the British Journal of Anaesthesia: a century of discovery and dissemination.
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Hemmings HC Jr and Lambert DG
- Subjects
- Humans, History, 20th Century, History, 21st Century, Publishing, Critical Care, Anesthesia, Anesthesiology history, Biomedical Research
- Abstract
In 2023, the British Journal of Anaesthesia commemorates its first century of publishing innovations in anaesthesia, pain, critical care and perioperative medicine. In honour of this special anniversary we outline a number of exciting initiatives to occur over the course of the year to commemorate this important milestone, and to highlight the many contributions that the British Journal of Anaesthesia has made to patient care, medical research, and medical education in our first 100 years., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2023
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33. Nociceptin/Orphanin FQ receptor expression in primary human umbilical vein endothelial cells is not regulated by exposure to breast cancer cell media or angiogenic stimuli.
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Giakomidi D, Khemiri S, Mahbuba W, McVey DG, Al-Janabi F, Guerrini R, Calo G, Ye S, and Lambert DG
- Abstract
Background: Opioid receptors are naloxone-sensitive (MOP [mu: μ], DOP [delta: δ], and KOP [kappa: κ]) and naloxone-insensitive Nociceptin/Orphanin FQ (N/OFQ) peptide receptor (NOP). Clinically, most opioid analgesics target MOP. Angiogenesis is the formation of new blood vessels and involves endothelial cell activation, proliferation, and migration. The effect of opioids on this process is controversial with no data for NOP receptor ligands., Methods: We used patient-derived human umbilical vein endothelial cells (HUVECs) treated with media from the Michigan Cancer Foundation-7 (MCF-7) breast cancer cells or vascular endothelial growth factor (VEGF; 10 ng ml
-1 ) and fibroblast growth factor (FGF; 10 ng ml-1 ) as angiogenic stimuli. We have measured (i) NOP/MOP messenger RNA, (ii) receptor protein using N/OFQATTO594 and DermorphinATTO488 as fluorescent probes for NOP and MOP, and (iii) NOP/MOP function in a wound healing assay (crude measure of migration that occurs during angiogenesis)., Results: HUVEC lines from 32 patients were used. Using all 32 lines, mRNA for NOP but not MOP was detected. This was unaffected by media from MCF-7 cells or VEGF/FGF. There was no binding of either N/OFQATTO594 (NOP) or DermorphinATTO488 (MOP) in the absence or presence of angiogenic stimuli (six lines tested). In the absence of MOP mRNA, this was expected. Whilst MCF-7 conditioned medium (not VEGF/FGF) reduced wound healing per se (14 lines tested), there was no effect of N/OFQ (NOP ligand) or morphine (MOP ligand)., Conclusions: Media from MCF-7 breast cancer cells or VEGF/FGF as angiogenic stimuli did not influence NOP translation into receptor protein. MOP was absent. In the absence of constitutive or inducible MOP/NOP, there was no effect on wound healing as a measure of angiogenesis., (© 2022 The Author(s).)- Published
- 2022
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34. Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors.
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Wtorek K, Ghidini A, Gentilucci L, Adamska-Bartłomiejczyk A, Piekielna-Ciesielska J, Ruzza C, Sturaro C, Calò G, Pieretti S, Kluczyk A, McDonald J, Lambert DG, and Janecka A
- Subjects
- Animals, Mice, Receptors, Opioid, kappa, Narcotic Antagonists pharmacology, Receptors, Opioid, mu agonists, Molecular Docking Simulation, Ligands, Dose-Response Relationship, Drug, Naloxone, Analgesics pharmacology, Peptides pharmacology, Chimera, Peptides, Cyclic, Analgesics, Opioid therapeutic use, Receptors, Opioid agonists
- Abstract
Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH
2 ( RP-170 ), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH2 , a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH2 ( KW-495 ) and RP-170-Gly3 -RYYRIK-NH2 ( KW-496 ). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly3 spacer.- Published
- 2022
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35. Ketamine; history and role in anesthetic pharmacology.
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Hirota K and Lambert DG
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- Analgesics, Opioid adverse effects, Humans, Hyperalgesia chemically induced, Phencyclidine, Remifentanil, Anesthetics pharmacology, Anesthetics therapeutic use, Ketamine pharmacology, Ketamine therapeutic use
- Abstract
Ketamine (Ket) was developed in 1962 as a less hallucinogenic and shorter acting agent than phencyclidine. It was given to humans for the first time in 1964. However, Ket produces several adverse reactions such as raised intracranial and blood pressures along with seizures, and patients still show low acceptance due to hallucinations. As new volatile and intravenous anesthetic agents with good emergence and favorable side effect profiles were developed, Ket use markedly decreased. In the 1990s, as the ultrashort-acting opioid remifentanil was developed, high dose opioid could be used to reduce surgical stress in highly invasive procedures. However, high dose opioids can produce hyperalgesia and acute tolerance. As Ket can exert anti-hyperalgesic actions, the clinical use of low dose Ket has been reconsidered. Other beneficial effects of Ket such as; analgesia, anti-shock in hemorrhagic and septic insults, anti-inflammatory effects, anti-tumor effects, brain and spinal cord neuroprotection, and bronchodilation, have all been reported. Moreover, this anesthetic agent at low dose has been recently recognized to possess anti-depressive actions. This diverse profile extends Ket far beyond anesthesia practice and the operating room., (Copyright © 2022. Published by Elsevier Ltd.)
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- 2022
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36. In vitro sepsis induces Nociceptin/Orphanin FQ receptor (NOP) expression in primary human vascular endothelial but not smooth muscle cells.
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Bird MF, Gallacher-Horley B, McDonald J, McVey DG, Al-Janabi F, Guerrini R, Calo G, Ye S, Thompson JP, and Lambert DG
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- Animals, Endothelial Cells, Humans, Lipopolysaccharides, Muscle Cells, Opioid Peptides, Peptidoglycan, RNA, Messenger, Receptors, Opioid, Nociceptin Receptor, Nociceptin, Hypotension, Sepsis
- Abstract
Sepsis is a dysregulated host response to infection that can cause widespread effects on other organs including cardiovascular depression, hypotension and organ failure. The receptor for Nociceptin/Orphanin FQ (N/OFQ), NOP is expressed on immune cells and these cells can release the peptide. Exogenous N/OFQ can dilate blood vessels and this peptide is increased in animal and human sepsis. We hypothesise that NOP receptors are present on vascular endothelial cells and therefore provide the target for released N/OFQ to cause vasodilation and hence hypotension. Using human umbilical vein endothelial cells (HUVEC) and human vascular smooth muscle cells (HVSMC) freshly prepared from umbilical cords and up to passage 4, we assessed NOP mRNA expression by Polymerase Chain Reaction (PCR), NOP surface receptor expression using a fluorescent NOP selective probe (N/OFQATTO594) and NOP receptor function with N/OFQ stimulated ERK1/2 phosphorylation. As an in vitro sepsis mimic we variably incubated cells with 100ng/ml Lipopolysaccharide and Peptidoglycan G (LPS/PepG). HUVECs express NOP mRNA and this was reduced by ~80% (n = 49) after 24-48 hours treatment with LPS/PepG. Untreated cells do not express surface NOP receptors but when treated with LPS/PepG the reduced mRNA was translated into protein visualised by N/OFQATTO594 binding (n = 49). These NOP receptors in treated cells produced an N/OFQ (1μM) driven increase in ERK1/2 phosphorylation (n = 20). One (of 50) HUVEC lines expressed NOP mRNA and receptor protein in the absence of LPS/PepG treatment. In contrast, HVSMC expressed NOP mRNA and surface receptor protein (n = 10) independently of LPS/PepG treatment. These receptors were also coupled to ERK1/2 where N/OFQ (1μM) increased phosphorylation. Collectively these data show that an in vitro sepsis mimic (LPS/PepG) upregulates functional NOP expression in the vascular endothelium. Activation of these endothelial receptors as suggested from in vivo whole animal work may contribute to the hypotensive response seen in sepsis. Moreover, blockade of these receptors might be a useful adjunct in the treatment of sepsis., Competing Interests: Declaration of interests: DGL is a scientific adviser to Cellomatics, a SME-CRO. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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- 2022
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37. A novel bioassay to detect Nociceptin/Orphanin FQ release from single human polymorphonuclear cells.
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Bird MF, Hebbes CP, Scott SWM, Willets J, Thompson JP, and Lambert DG
- Subjects
- Animals, Biological Assay, CHO Cells, Cricetinae, Cricetulus, Humans, Opioid Peptides, Nociceptin, Calcium, Receptors, Opioid metabolism
- Abstract
Nociceptin/Orphanin FQ (N/OFQ) is the endogenous opioid agonist for the N/OFQ receptor or NOP. This receptor system is involved in pain processing but also has a role in immune regulation. Indeed, polymorphonuclear cells (PMNs) express mRNA for N/OFQ precursor and are a potential source for circulating N/OFQ. Current measurements are based on ELISA and RIA techniques. In this study we have designed a bioassay to measure N/OFQ release from single PMNs. Chinese Hamster Ovary (CHO) cells transfected with the human (h) NOP receptor and Gαiq5 chimera force receptor coupling in biosensor cells to increase intracellular Ca2+; this can be measured with FLUO-4 dye. If isolated PMNs from healthy human volunteers are layered next to CHOhNOPGαiq5 biosensor cells then stimulated with the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP) we hypothesise that released N/OFQ will activate the biosensor. PMNs also release ATP and CHO cells express purinergic receptors coupled to elevated Ca2+. In a system where these receptors (P2Y1, P2Y2 and P2X7) are blocked with high concentrations of PPADS and oATP, PMN stimulation with fMLP increases Ca2+ in PMNs then shortly afterwards the biosensor cells. Our data therfore reports detection of single cell N/OFQ release from immune cells. This was absent when cells were preincubated with the selective NOP antagonist; SB-612111. Collectively this is the first description of single cell N/OFQ release. We will deploy this assay with further purified individual cell types and use this to further study the role of the N/OFQ-NOP system in disease; in particular sepsis where there is strong evidence for increased levels of N/OFQ worsening outcome., Competing Interests: DGL is a scientific adviser to Cellomatics, a SME-CRO. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2022
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38. Inter-lateral Referral of Sensation in Health and Disease Using a Mirror Illusion-A Scoping Review.
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Hagenberg A, Lambert DG, Jussab S, Maltby J, and Robinson TG
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- Cross-Sectional Studies, Humans, Neuropsychological Tests, Referral and Consultation, Touch physiology, Illusions physiology
- Abstract
Objective: Perception of touch is expected at the location where it is applied. However, there are indications that being touched may be perceived on the contralateral side when seen as a reflection in a mirror at midline. Such inter-lateral referral of sensation (RS) lacks evidence, as mirror therapy research usually focusses on movement-based techniques. This study aimed to map out existing research across disciplines regarding the effect of RS in health and disease, and to understand whether there is rehabilitation potential in RS., Method: A scoping review was conducted to map out concepts and keywords across disciplines interested in this topic, using keywords in several languages, and a wide range of databases and additional sources., Results: The review revealed mostly cross-sectional experiments and included over 486 participants: healthy, or with stroke, complex regional pain syndrome, amputation, nerve graft surgery or radial fracture. Procedures varied regarding stimulation tool, time and location, with two stimulating replacements, one the face and one a variety of areas. Response rates ranged from 0 to 100%.In general, RS was regarded as a phenomenon or even as a predictor of maladaptive neuroplasticity. There was little research into using RS stimulation as a modulatory tool to improve sensory perception., Conclusions: RS challenges the understanding of touch perception and elicits a range of questions regarding neuro-processing. A modulatory approach using RS has not been described, requires investigation and, if promising, development as an intervention., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
- Published
- 2022
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39. Opioids and cancer survival: are we looking in the wrong place?
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Giakomidi D, Bird MF, and Lambert DG
- Abstract
There is a controversial narrative in the anaesthetic literature suggesting that anaesthetic technique (including opioids) may be detrimental to survival after tumour resection. The initial observations were retrospective. Several prospective studies are ongoing; one in breast cancer has reported no adverse outcome. The evidence for an effect of opioids stems from three pieces of information: (1) opioids depress the immune system, (2) opioids potentially promote angiogenesis, and (3) opioids potentially support tumour growth. Although the evidence for (2)/(3) is unclear, combinations of these effects are beneficial to tumours and potentially promote metastatic reseeding. Accepted wisdom suggests that opioid effects are driven by opioid receptor activation but the presence of opioid receptors on immune cells for example is unlikely. Immune cells, vascular endothelium and a range of tumour cells express Toll-like receptor 4 (TLR4) receptors (for Gram-negative bacterial wall components), and there is growing evidence for opioids interacting with this alternative receptor; and for some there is paradoxical naloxone sensitivity. Is the focus on opioid receptors and cancer the wrong target? TLR4 receptor activation produces immune activation, stimulates angiogenesis, and supports tumour survival. We know that some opioids are more immune suppressive than others (there is no such comparative information for angiogenesis and tumour survival); this may correlate with TLR4 activation. If there are clusters of opioids that have more opioid than TLR4 profiles and vice versa , this may influence outcome. If this is the case, then evidence-based advice could be given for perioperative use in the oncology-anaesthesia setting., Competing Interests: DGL is chair of the board of British Journal of Anaesthesia and scientific adviser to Cellomatics, a SME-CRO. None of the remaining authors have conflicts to declare., (© 2022 The Authors.)
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- 2022
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40. Preclinical discovery and development of oliceridine (Olinvyk®) for the treatment of post-operative pain.
- Author
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Azzam AAH and Lambert DG
- Subjects
- Analgesics, Opioid adverse effects, Humans, Morphine adverse effects, Pain, Postoperative drug therapy, Spiro Compounds adverse effects, Thiophenes adverse effects
- Abstract
Introduction: Opioids acting at the MOP (mu:µ) receptor produce analgesia but also side effects. There is debate suggesting opioid receptors produce analgesia via G-protein and side-effects via β-arrestin-2 pathways. Opioids targeting G-proteins over the arrestins (bias) offer potential therapeutic advantages. Oliceridine is a putative MOP, G-protein biased agonist., Areas Covered: Oliceridine is selective for MOP receptors with greater activity at G-proteins over arrestins. A substantial body of evidence now points to a simpler pharmacological descriptor of partial agonist. Preclinical in vivo data indicates a robust antinociceptive response of shorter duration than morphine. Apollo trials (Phase-III RCT-bunionectomy/abdominoplasty) describe good analgesic efficacy that was non-inferior to morphine with good tolerability and side-effect profile. There is evidence for an improved respiratory safety profile. Oliceridine is approved by the FDA., Expert Opinion: Oliceridine will be an important addition to the clinical armamentarium for use for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Respiratory advantage and the possibility of reduced abuse potential are possible advantages over the use of traditional opioids. Based on a number of excellent, highly detailed studies, oliceridine should be described as a partial agonist; this 'label' does not matter.
- Published
- 2022
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41. MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands.
- Author
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Bird MF, McDonald J, Horley B, O'Doherty JP, Fraser B, Gibson CL, Guerrini R, Caló G, and Lambert DG
- Subjects
- Humans, Ligands, HEK293 Cells, Animals, Protein Binding, Cyclic AMP metabolism, Neurons metabolism, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Peptides metabolism, Peptides chemistry, Peptides pharmacology, Receptors, Opioid metabolism, Receptors, Opioid, mu metabolism, Opioid Peptides metabolism, Opioid Peptides pharmacology, Nociceptin Receptor
- Abstract
Opioids targeting mu;μ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2022
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42. Drug-receptor interactions in anaesthesia.
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McDonald J and Lambert DG
- Abstract
Competing Interests: DGL is chair of the board of the British Journal of Anaesthesia, He is also a non-executive director of Cellomatics and has previously has held consultancy and received funding from Grunenthal. JM declares no conflicts of interest.
- Published
- 2022
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43. Fluorescent opioid receptor ligands as tools to study opioid receptor function.
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Giakomidi D, Bird MF, Guerrini R, Calo G, and Lambert DG
- Subjects
- Fluorescent Dyes, Ligands, Receptors, Opioid, mu, Analgesics, Opioid, Receptors, Opioid
- Abstract
Opioid receptors are divided into the three classical types: MOP(μ:mu), DOP(δ:delta) and KOP(κ:kappa) that are naloxone-sensitive and an additional naloxone-insensitive nociceptin/orphanin FQ(N/OFQ) peptide receptor(NOP). Studies to determine opioid receptor location and turnover variably rely on; (i) measuring receptor mRNA, (ii) genetically tagging receptors, (iii) labelling receptors with radioligands, (iv) use of antibodies in immunohistochemistry/Western Blotting or (v) measuring receptor function coupled with the use of selective antagonists. All have their drawbacks with significant issues relating to mRNA not necessarily predicting protein, poor antibody selectivity and utility of radiolabels in low expression systems. In this minireview we discuss use of fluorescently labelled opioid receptor ligands. To maintain the pharmacological properties of the corresponding parent ligand fluorescently labelled ligands must take into account fluorophore (brightness and propensity to bleach), linker length and chemistry, and site to which the linker (and hence probe) will be attached. Use of donor and acceptor fluorophores with spectral overlap facilitates use in FRET type assays to determine proximity of ligand or tagged receptor pairs. There is a wide range of probes of agonist and antagonist nature for all four opioid receptor types; caution is needed with agonist probes due to the possibility for internalization. We have produced two novel ATTO based probes; Dermorphin
ATTO488 (MOP) and N/OFQATTO594 (NOP). These probes label MOP and NOP in a range of preparations and using N/OFQATTO594 we demonstrate internalization and ligand-receptor interaction by FRET. Fluorescent opioid probes offer potential methodological advantages over more traditional use of antibodies and radiolabels., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2022
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44. Anaesthesia-related drugs and SARS-CoV-2 infection.
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Hirota K and Lambert DG
- Subjects
- Anesthetics administration & dosage, COVID-19 surgery, Humans, SARS-CoV-2 drug effects, Anesthetics metabolism, COVID-19 metabolism, SARS-CoV-2 metabolism
- Abstract
Competing Interests: Declarations of interest DGL is Chairman of BJA. KH has no conflicts of interest to declare.
- Published
- 2021
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45. Evaluation of [Cys(ATTO 488)8]Dermorphin-NH2 as a novel tool for the study of μ-opioid peptide receptors.
- Author
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Giakomidi D, Bird MF, McDonald J, Marzola E, Guerrini R, Chanoch S, Sabu N, Horley B, Calo G, and Lambert DG
- Subjects
- Animals, CHO Cells, Cricetulus, HEK293 Cells, Humans, Phosphorylation, Cell Membrane metabolism, Opioid Peptides, Receptors, Opioid, mu metabolism
- Abstract
The μ-opioid peptide (MOP) receptor is a member of the opioid receptor family and an important clinical target for analgesia. Measuring MOP receptor location and tracking its turnover traditionally used radiolabels or antibodies with attendant problems of utility of radiolabels in whole cells and poor antibody selectivity. To address these issues we have synthesized and characterised a novel ATTO488 based fluorescent Dermorphin analogue; [Cys(ATTO 488)8]Dermorphin-NH2 (DermATTO488). We initially assessed the binding profile of DermATTO488 in HEK cells expressing human MOP and CHO cells expressing human MOP, δ-opioid peptide (DOP), κ-opioid peptide (KOP) and Nociceptin/Orphanin FQ peptide (NOP) receptors using radioligand binding. Functional activity of the conjugated peptide was assessed by measuring (i) the ability of the ligand to engage G-protein by measuring the ability to stimulate GTPγ[35S] binding and (ii) the ability to stimulate phosphorylation of ERK1/2. Receptor location was visualised using confocal scanning laser microscopy. Dermorphin and DermATTO488 bound to HEKMOP (pKi: 8.29 and 7.00; p<0.05), CHOMOP (pKi: 9.26 and 8.12; p<0.05) and CHODOP (pKi: 7.03 and 7.16; p>0.05). Both ligands were inactive at KOP and NOP. Dermorphin and DermATTO488 stimulated the binding of GTPγ[35S] with similar pEC50 (7.84 and 7.62; p>0.05) and Emax (1.52 and 1.34fold p>0.05) values. Moreover, Dermorphin and DermATTO488 produced a monophasic stimulation of ERK1/2 phosphorylation peaking at 5mins (6.98 and 7.64-fold; p>0.05). Finally, in confocal microscopy DermATTO488 bound to recombinant MOP receptors on CHO and HEK cells in a concentration dependent manner that could be blocked by pre-incubation with unlabelled Dermorphin or Naloxone. Collectively, addition to ATTO488 to Dermorphin produced a ligand not dissimilar to Dermorphin; with ~10fold selectivity over DOP. This new ligand DermATTO488 retained functional activity and could be used to visualise MOP receptor location., Competing Interests: In the past DGL has held consultancy with Grunenthal (this does not alter our adherence to PLOS ONE policies on sharing data and materials) and is a non-executive director of the SME-CRO; Cellomatics. None of the remaining authors have conflicts to declare.
- Published
- 2021
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46. Pharmacological Characterization of µ-Opioid Receptor Agonists with Biased G Protein or β-Arrestin Signaling, and Computational Study of Conformational Changes during Receptor Activation.
- Author
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Piekielna-Ciesielska J, Artali R, Azzam AAH, Lambert DG, Kluczyk A, Gentilucci L, and Janecka A
- Subjects
- Animals, CHO Cells, Cricetulus, Drug Discovery, Humans, Ligands, Magnetic Resonance Spectroscopy, Molecular Docking Simulation, Molecular Dynamics Simulation, Molecular Structure, GTP-Binding Proteins metabolism, Models, Molecular, Molecular Conformation, Receptors, Opioid, mu agonists, Receptors, Opioid, mu chemistry, Signal Transduction drug effects, beta-Arrestins metabolism
- Abstract
In recent years, G protein vs. β-arrestin biased agonism at opioid receptors has been proposed as an opportunity to produce antinociception with reduced adverse effects. However, at present this approach is highly debated, a reason why more information about biased ligands is required. While the practical relevance of bias in the case of µ-opioid receptors (MOP) still needs to be validated, it remains important to understand the basis of this bias of MOP (and other GPCRs). Recently, we reported two cyclopeptides with high affinity for MOP, the G protein biased Dmt-c[d-Lys-Phe- p CF
3 -Phe-Asp]NH2 (F-81), and the β-arrestin 2 biased Dmt-c[d-Lys-Phe-Asp]NH2 (C-33), as determined by calcium mobilization assay and bioluminescence resonance energy transfer-based assay. The biased character of F-81 and C-33 has been further analyzed in the [35 S]GTPγS binding assay in human MOP-expressing cells, and the PathHunter enzyme complementation assay, used to measure β-arrestin 2 recruitment. To investigate the structural features of peptide-MOP complexes, we performed conformational analysis by NMR spectroscopy, molecular docking, and molecular dynamics simulation. These studies predicted that the two ligands form alternative complexes with MOP, engaging specific ligand-receptor contacts. This would induce different displays of the cytosolic side of the seven-helices bundle, in particular by stabilizing different angulations of helix 6, that could favor intracellular coupling to either G protein or β-arrestin.- Published
- 2020
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47. Propofol and SARS-CoV-2 infection.
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Hirota K and Lambert DG
- Subjects
- COVID-19, Critical Illness, Drug Repositioning, Humans, Pandemics, Anesthetics, Intravenous therapeutic use, Coronavirus Infections drug therapy, Hypnotics and Sedatives therapeutic use, Pneumonia, Viral drug therapy, Propofol therapeutic use
- Abstract
Competing Interests: Declarations of interest KH declares no conflicts of interest. DG Lambert is Chairman of BJA.
- Published
- 2020
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48. Opioids and the COVID-19 pandemic: does chronic opioid use or misuse increase clinical vulnerability?
- Author
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Lambert DG
- Subjects
- Analgesics, Opioid adverse effects, COVID-19, Humans, Pain Management, Respiratory Insufficiency chemically induced, Analgesics, Opioid therapeutic use, Coronavirus Infections, Opioid Epidemic, Pandemics, Pneumonia, Viral, Prescription Drug Misuse statistics & numerical data
- Published
- 2020
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49. Biased versus Partial Agonism in the Search for Safer Opioid Analgesics.
- Author
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Azevedo Neto J, Costanzini A, De Giorgio R, Lambert DG, Ruzza C, and Calò G
- Subjects
- Animals, Drug Evaluation, Preclinical, Humans, Mice, Mice, Knockout, Pain genetics, Pain metabolism, Pain pathology, beta-Arrestin 2 agonists, beta-Arrestin 2 genetics, beta-Arrestin 2 metabolism, Analgesics, Opioid chemistry, Analgesics, Opioid therapeutic use, Drug Approval, Pain drug therapy
- Abstract
Opioids such as morphine-acting at the mu opioid receptor-are the mainstay for treatment of moderate to severe pain and have good efficacy in these indications. However, these drugs produce a plethora of unwanted adverse effects including respiratory depression, constipation, immune suppression and with prolonged treatment, tolerance, dependence and abuse liability. Studies in β-arrestin 2 gene knockout (βarr2(-/-)) animals indicate that morphine analgesia is potentiated while side effects are reduced, suggesting that drugs biased away from arrestin may manifest with a reduced-side-effect profile. However, there is controversy in this area with improvement of morphine-induced constipation and reduced respiratory effects in βarr2(-/-) mice. Moreover, studies performed with mice genetically engineered with G-protein-biased mu receptors suggested increased sensitivity of these animals to both analgesic actions and side effects of opioid drugs. Several new molecules have been identified as mu receptor G-protein-biased agonists, including oliceridine (TRV130), PZM21 and SR-17018. These compounds have provided preclinical data with apparent support for bias toward G proteins and the genetic premise of effective and safer analgesics. There are clinical data for oliceridine that have been very recently approved for short term intravenous use in hospitals and other controlled settings. While these data are compelling and provide a potential new pathway-based target for drug discovery, a simpler explanation for the behavior of these biased agonists revolves around differences in intrinsic activity. A highly detailed study comparing oliceridine, PZM21 and SR-17018 (among others) in a range of assays showed that these molecules behave as partial agonists. Moreover, there was a correlation between their therapeutic indices and their efficacies, but not their bias factors. If there is amplification of G-protein, but not arrestin pathways, then agonists with reduced efficacy would show high levels of activity at G-protein and low or absent activity at arrestin; offering analgesia with reduced side effects or 'apparent bias'. Overall, the current data suggests-and we support-caution in ascribing biased agonism to reduced-side-effect profiles for mu-agonist analgesics.
- Published
- 2020
- Full Text
- View/download PDF
50. Functional nociceptin receptors are upregulated on human umbilical vein endothelial cells during experimental in vitro sepsis.
- Author
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Bird MF, McDonald J, Gallacher-Horley B, Guerrini R, Calo G, Ye S, Thompson JP, and Lambert DG
- Published
- 2020
- Full Text
- View/download PDF
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