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Article: ALK5 inhibition in renal disease.

Laping, Nicholas J

2003 Volume 3, Issue 2, Page(s) 204–208

Abstract: Recent advances have identified novel small molecule inhibitors of the transforming growth factor-beta (TGF-beta) type I receptor kinase as a potential therapy in organ remodeling diseases, such as chronic renal disease. Because TGF-beta is central to ... ...

Abstract	Recent advances have identified novel small molecule inhibitors of the transforming growth factor-beta (TGF-beta) type I receptor kinase as a potential therapy in organ remodeling diseases, such as chronic renal disease. Because TGF-beta is central to the progression of fibrosis, selective inhibition of this signaling pathway could provide a novel treatment in many fibrotic diseases. The rationale for inhibition of TGF-beta signaling in renal disease includes prevention of fibrosis, tubular dedifferentiation and vascular effects.
MeSH term(s)	Activin Receptors, Type I/antagonists & inhibitors ; Activin Receptors, Type I/physiology ; Animals ; Humans ; Kidney Diseases/drug therapy ; Kidney Diseases/metabolism ; Protein-Serine-Threonine Kinases ; Receptor, Transforming Growth Factor-beta Type I ; Receptors, Transforming Growth Factor beta/antagonists & inhibitors ; Receptors, Transforming Growth Factor beta/physiology ; Signal Transduction/drug effects ; Signal Transduction/physiology
Chemical Substances	Receptors, Transforming Growth Factor beta ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Activin Receptors, Type I (EC 2.7.11.30) ; Receptor, Transforming Growth Factor-beta Type I (EC 2.7.11.30) ; TGFBR1 protein, human (EC 2.7.11.30)
Language	English
Publishing date	2003-02-27
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/s1471-4892(03)00002-x
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Article ; Online: Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy.

International journal of molecular sciences

2021 Volume 22, Issue 3

Abstract: Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is ... ...

Abstract	Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer's disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.
MeSH term(s)	Animals ; Brain/metabolism ; Brain/pathology ; Disease Models, Animal ; Hippocampus/drug effects ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Mice ; Mice, Transgenic ; Neurodegenerative Diseases/diagnosis ; Neurodegenerative Diseases/drug therapy ; Neurodegenerative Diseases/etiology ; Neurodegenerative Diseases/metabolism ; Neurons/drug effects ; Neurons/metabolism ; Phosphorylation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proteome ; Proteomics/methods ; Severity of Illness Index ; Tauopathies/diagnosis ; Tauopathies/drug therapy ; Tauopathies/etiology ; Tauopathies/metabolism ; Unfolded Protein Response ; eIF-2 Kinase/metabolism ; tau Proteins/metabolism
Chemical Substances	Protein Kinase Inhibitors ; Proteome ; tau Proteins ; EIF2AK3 protein, human (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1)
Language	English
Publishing date	2021-01-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22031186
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Article ; Online: Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

International Journal of Molecular Sciences, Vol 22, Iss 3, p

2021 Volume 1186

Abstract	Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562.
Keywords	tau ; GSK2606414 ; kinases ; MEMRI ; TMT proteomics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	616
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Effect of estrogen and progesterone on urodynamics in the conscious rat.

Patra, Phani B / Thorneloe, Kevin S / Laping, Nicholas J

Urology

2009 Volume 74, Issue 2, Page(s) 463–466

Abstract: Objectives: To examine the effects of estrogen and/or progesterone on the cystometric profiles obtained using continuous-filling cystometry in the conscious Sprague-Dawley rat.: Methods: Sprague-Dawley rats underwent ovariectomy (OVX) and were ... ...

Abstract	Objectives: To examine the effects of estrogen and/or progesterone on the cystometric profiles obtained using continuous-filling cystometry in the conscious Sprague-Dawley rat. Methods: Sprague-Dawley rats underwent ovariectomy (OVX) and were compared with controls by conscious continuous-filling cystometry. The effect of estrogen (10 microg/kg/d for 14 days) and/or progesterone (10 mg/kg/d for 14 days) replacement on OVX urodynamics was examined (n = 7-8/group). Results: OVX rats demonstrated reduced micturition intervals and voided volumes compared with controls. These effects of OVX were reversed by estrogen replacement, but not by progesterone replacement. When combined with estrogen, progesterone functioned to partially antagonize the effects of estrogen in OVX rats. Conclusions: Estrogen enhances bladder capacity in the OVX rat and therefore is a likely contributor to the larger bladder capacity in the female compared with the male rat. Consistent with its established role in reproductive physiology, progesterone antagonizes the beneficial effects of estrogen on OVX rat urodynamics.
MeSH term(s)	Animals ; Estrogens/pharmacology ; Estrogens/physiology ; Female ; Ovariectomy ; Progesterone/pharmacology ; Progesterone/physiology ; Rats ; Rats, Sprague-Dawley ; Urinary Bladder/physiology ; Urodynamics/drug effects ; Urodynamics/physiology
Chemical Substances	Estrogens ; Progesterone (4G7DS2Q64Y)
Language	English
Publishing date	2009-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	192062-5
ISSN	1527-9995 ; 0090-4295
ISSN (online)	1527-9995
ISSN	0090-4295
DOI	10.1016/j.urology.2008.12.046
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Zs.A 1142: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Role of spinal Cav2.2 and Cav2.1 ion channels in bladder nociception.

Su, Xin / Leon, Lisa A / Laping, Nicholas J

The Journal of urology

2008 Volume 179, Issue 6, Page(s) 2464–2469

Abstract: Purpose: High voltage activated calcium channels have been implicated in nociceptive transmission in several animal pain models. To our knowledge this is the first study to evaluate the ability of various high voltage activated calcium channel blockers ... ...

Abstract	Purpose: High voltage activated calcium channels have been implicated in nociceptive transmission in several animal pain models. To our knowledge this is the first study to evaluate the ability of various high voltage activated calcium channel blockers to inhibit the transmission of noxious stimuli from the bladder at the level of the spinal cord. Materials and methods: The nociceptive response was measured by analyzing the visceromotor reflex and cardiovascular (pressor) responses to bladder distention. The role of Cav2.2 (N-type), Cav2.1 (P/Q-type) and Cav1 (L-type) calcium channels in bladder nociceptive reflex responses was examined using omega-conotoxin-GVIA, omega-agatoxin IVA/omega-conotoxin MVIIC and verapamil (Sigma-Aldrich), respectively. Female Sprague-Dawley rats were acutely instrumented with intrathecal catheters, carotid arterial and bladder cannulas. Needle electrodes were placed directly into the abdominal musculature to measure myoelectric activity subsequent to repeat phasic bladder distention at 60 mm Hg for 30 seconds at 3-minute intervals with the rats under 1% isoflurane. Drugs were administered by intrathecal injection 2 minutes before distention and responses were recorded for 15 minutes per dose. Results: When administered intrathecally, omega-conotoxin-GVIA and omega-conotoxin MVIIC (10 microg/kg each) significantly attenuated reflex responses to noxious bladder distention to 12% and 65% of the maximal visceromotor reflex response, and to 45% and 59% of the control pressor response, respectively. However, agatoxin and verapamil were less effective. Conclusions: The study suggests that spinal Cav2.2 and Q-type Cav2.1 calcium channels contribute to acute bladder nociception, while Cav1 channels have a limited role.
MeSH term(s)	Animals ; Calcium Channel Blockers/pharmacology ; Calcium Channels, N-Type/drug effects ; Calcium Channels, N-Type/physiology ; Conotoxins/pharmacology ; Female ; Nociceptors/physiology ; Rats ; Rats, Sprague-Dawley ; Reflex/drug effects ; Reflex/physiology ; Spinal Cord/physiology ; Urinary Bladder/physiology ; omega-Agatoxin IVA/pharmacology ; omega-Conotoxin GVIA/pharmacology
Chemical Substances	Cacna1b protein, rat ; Calcium Channel Blockers ; Calcium Channels, N-Type ; Conotoxins ; omega-Agatoxin IVA ; voltage-dependent calcium channel (P-Q type) ; omega-conotoxin MVIID (153887-08-2) ; omega-Conotoxin GVIA (92078-76-7)
Language	English
Publishing date	2008-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	3176-8
ISSN	1527-3792 ; 0022-5347
ISSN (online)	1527-3792
ISSN	0022-5347
DOI	10.1016/j.juro.2008.01.088
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Ui VI Zs.91: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 331: Show issues

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Article ; Online: PERK inhibition delays neurodegeneration and improves motor function in a mouse model of Marinesco-Sjögren syndrome.

Grande, Valentina / Ornaghi, Francesca / Comerio, Liliana / Restelli, Elena / Masone, Antonio / Corbelli, Alessandro / Tolomeo, Daniele / Capone, Vanessa / Axten, Jeffrey M / Laping, Nicholas J / Fiordaliso, Fabio / Sallese, Michele / Chiesa, Roberto

Human molecular genetics

2018 Volume 27, Issue 14, Page(s) 2477–2489

Abstract: Marinesco-Sjögren syndrome (MSS) is a rare, early onset, autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts and myopathy. Most MSS cases are caused by loss-of-function mutations in the gene encoding SIL1, a nucleotide ... ...

Abstract	Marinesco-Sjögren syndrome (MSS) is a rare, early onset, autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts and myopathy. Most MSS cases are caused by loss-of-function mutations in the gene encoding SIL1, a nucleotide exchange factor for the molecular chaperone BiP which is essential for correct protein folding in the endoplasmic reticulum. Woozy mice carrying a spontaneous Sil1 mutation recapitulate key pathological features of MSS, including cerebellar atrophy with degeneration of Purkinje cells and progressive myopathy. Because the PERK branch of the unfolded protein response is activated in degenerating neurons of woozy mice, and inhibiting PERK-mediated translational attenuation has shown protective effects in protein-misfolding neurodegenerative disease models, we tested the therapeutic efficacy of GSK2606414, a potent inhibitor of PERK. Mice were chronically treated with GSK2606414 starting from a presymptomatic stage, and the effects were evaluated on biochemical, histopathological and clinical readouts. GSK2606414 delayed Purkinje cell degeneration and the onset of motor deficits, prolonging the asymptomatic phase of the disease; it also reduced the skeletal muscle abnormalities and improved motor performance during the symptomatic phase. The protein but not the mRNA level of ORP150, a nucleotide exchange factor which can substitute for SIL1, was increased in the cerebellum of GSK2606414-treated woozy mice, suggesting that translational recovery promoted the synthesis of this alternative BiP co-factor. Targeting PERK signaling may have beneficial disease-modifying effects in carriers of SIL1 mutations.
MeSH term(s)	Adenine/administration & dosage ; Adenine/analogs & derivatives ; Animals ; Cerebellum/drug effects ; Cerebellum/physiopathology ; Disease Models, Animal ; Endoplasmic Reticulum/genetics ; Endoplasmic Reticulum/pathology ; Guanine Nucleotide Exchange Factors/genetics ; HSP70 Heat-Shock Proteins/genetics ; Heterozygote ; Humans ; Indoles/administration & dosage ; Loss of Function Mutation/genetics ; Mice ; Motor Activity/physiology ; Nerve Degeneration/genetics ; Nerve Degeneration/physiopathology ; Protein Folding ; Purkinje Cells/drug effects ; Purkinje Cells/pathology ; Spinocerebellar Degenerations/genetics ; Spinocerebellar Degenerations/pathology ; Spinocerebellar Degenerations/therapy ; Unfolded Protein Response/genetics ; eIF-2 Kinase/genetics
Chemical Substances	7-methyl-5-(1-((3-(trifluoromethyl)phenyl)acetyl)-2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo(2,3-d)pyrimidin-4-amine ; Guanine Nucleotide Exchange Factors ; HSP70 Heat-Shock Proteins ; Indoles ; SIL1 protein, human ; SIL1 protein, mouse ; oxygen-regulated proteins ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1) ; Adenine (JAC85A2161)
Language	English
Publishing date	2018-04-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddy152
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Article: TLR2 agonism reverses chemotherapy-induced neutropenia in

Laping, Nicholas J / DeMartino, Michael P / Cottom, Joshua E / Axten, Jeffrey M / Emery, John G / Guss, Jeffrey H / Burman, Miriam / Foley, James J / Cheung, Mui / Oliff, Allen / Kumar, Sanjay

Blood advances

2017 Volume 1, Issue 26, Page(s) 2553–2562

Abstract: Neutropenia is a common consequence of radiation and chemotherapy in cancer patients. The resulting immunocompromised patients become highly susceptible to potentially life-threatening infections. Granulocyte colony-stimulating factor (G-CSF) is known to ...

Abstract	Neutropenia is a common consequence of radiation and chemotherapy in cancer patients. The resulting immunocompromised patients become highly susceptible to potentially life-threatening infections. Granulocyte colony-stimulating factor (G-CSF) is known to stimulate neutrophil production and is widely used as a treatment of chemotherapy-induced neutropenia. A small-molecule G-CSF secretagogue without a requirement for refrigerated supply chain would offer a more convenient and cost-effective treatment of chemotherapy-induced neutropenia. Bacterial lipopeptides activate innate immune responses through Toll-like receptor 2 (TLR2) and induce the release of cytokines, including G-CSF, from macrophages, monocytes, and endothelial. Pam
Language	English
Publishing date	2017-12-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	2876449-3
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2017010611
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Article ; Online: Evaluation of pressor and visceromotor reflex responses to bladder distension in urethane anesthetized rats.

Blatt, Lauren K / Lashinger, Erin S R / Laping, Nicholas J / Su, Xin

Neurourology and urodynamics

2009 Volume 28, Issue 5, Page(s) 442–446

Abstract: Aims: We tested cardiovascular and visceromotor reflex (VMR) responses to urinary bladder distension (UBD) in urethane anesthetized rats to see if it can replicate the response pattern and the inhibition of bladder nociceptive transmission by analgesics ...

Abstract	Aims: We tested cardiovascular and visceromotor reflex (VMR) responses to urinary bladder distension (UBD) in urethane anesthetized rats to see if it can replicate the response pattern and the inhibition of bladder nociceptive transmission by analgesics seen in isoflurane anesthetized animals. Methods: Female Sprague-Dawley rats under 3% isoflurane anesthesia were acutely instrumented with jugular venous, carotid arterial, and bladder cannulas for drug administration, blood pressure (BP) measurement, and bladder distension, respectively. Needle electrodes were placed directly into the abdominal musculature to measure myoelectrical activity subsequent to phasic UBD (30 sec in 3 min intervals). A cardiovascular response (pressor) and a VMR response (a contraction of abdominal and hind limb musculature) to UBD were evaluated in urethane (1.2 g/kg, i.v.) or isoflurane (1%) anesthetized rats. Results: Pressor and VMR responses to noxious UBD (60 mmHg) were generated under both anesthesics. The thresholds of stimulus response functions for both pressor and VMR responses were not affected by either anesthesics. However, the magnitude of the maximal pressor response was significantly reduced in urethane anesthesia. The analgesics, morphine, and mexiletine, significantly inhibited the VMR response to noxious UBD under both anesthetics, but the intensities of the inhibition from both analgesics under urethane anesthesia were much lower than under isoflurane anesthesia (ID50: 2.07 mg/kg vs. 0.88 mg/kg for morphine, >10 mg/kg vs. 0.47 mg/kg for mexiletine). Conclusions: The rat urinary bladder distension model in urethane anesthetized rats demonstrates a blunted maximal pressor response and a reduced inhibition of visceral nociceptive transmission by analgesics. Neurourol. Urodynam. 28:442-446, 2009. (c) 2008 Wiley-Liss, Inc.
MeSH term(s)	Abdominal Muscles/innervation ; Analgesics/pharmacology ; Anesthetics, Inhalation/pharmacology ; Anesthetics, Intravenous/pharmacology ; Animals ; Blood Pressure/drug effects ; Cardiovascular System/innervation ; Dose-Response Relationship, Drug ; Electromyography ; Female ; Isoflurane/pharmacology ; Mechanotransduction, Cellular/drug effects ; Mexiletine/pharmacology ; Morphine/pharmacology ; Muscle Contraction/drug effects ; Pressure ; Rats ; Rats, Sprague-Dawley ; Reflex/drug effects ; Urethane/pharmacology ; Urinary Bladder/innervation
Chemical Substances	Analgesics ; Anesthetics, Inhalation ; Anesthetics, Intravenous ; Mexiletine (1U511HHV4Z) ; Urethane (3IN71E75Z5) ; Morphine (76I7G6D29C) ; Isoflurane (CYS9AKD70P)
Language	English
Publishing date	2009
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	604904-7
ISSN	1520-6777 ; 0733-2467
ISSN (online)	1520-6777
ISSN	0733-2467
DOI	10.1002/nau.20650
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Article ; Online: Sustained elevation of MG53 in the bloodstream increases tissue regenerative capacity without compromising metabolic function.

Nature communications

2019 Volume 10, Issue 1, Page(s) 4659

Abstract: MG53 is a muscle-specific TRIM-family protein that presides over the cell membrane repair response. Here, we show that MG53 present in blood circulation acts as a myokine to facilitate tissue injury-repair and regeneration. Transgenic mice with sustained ...

Abstract	MG53 is a muscle-specific TRIM-family protein that presides over the cell membrane repair response. Here, we show that MG53 present in blood circulation acts as a myokine to facilitate tissue injury-repair and regeneration. Transgenic mice with sustained elevation of MG53 in the bloodstream (tPA-MG53) have a healthier and longer life-span when compared with littermate wild type mice. The tPA-MG53 mice show normal glucose handling and insulin signaling in skeletal muscle, and sustained elevation of MG53 in the bloodstream does not have a deleterious impact on db/db mice. More importantly, the tPA-MG53 mice display remarkable dermal wound healing capacity, enhanced muscle performance, and improved injury-repair and regeneration. Recombinant human MG53 protein protects against eccentric contraction-induced acute and chronic muscle injury in mice. Our findings highlight the myokine function of MG53 in tissue protection and present MG53 as an attractive biological reagent for regenerative medicine without interference with glucose handling in the body.
MeSH term(s)	Animals ; Calcium/metabolism ; Glucose/metabolism ; Glucose Tolerance Test ; Insulin/metabolism ; Membrane Proteins/blood ; Membrane Proteins/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle, Skeletal/metabolism ; Regeneration/genetics ; Systems Biology ; Wound Healing
Chemical Substances	Insulin ; MG53 protein, mouse ; Membrane Proteins ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2019-10-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-12483-0
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Article: Pharmacologic evaluation of pressor and visceromotor reflex responses to bladder distension.

Su, Xin / Riedel, Erin S / Leon, Lisa A / Laping, Nicholas J

Neurourology and urodynamics

2008 Volume 27, Issue 3, Page(s) 249–253

Abstract: Aims: Several mechanisms that are involved in acute rat bladder nociception were examined. The nociceptive response was measured by analyzing both cardiovascular and visceromotor reflex responses to urinary bladder distension. The contributions of micro- ...

Abstract	Aims: Several mechanisms that are involved in acute rat bladder nociception were examined. The nociceptive response was measured by analyzing both cardiovascular and visceromotor reflex responses to urinary bladder distension. The contributions of micro-opioid receptor, kappa-opioid receptor, sodium channels, muscarinic receptors, and cyclooxygenase, were explored with morphine, U50,488, mexiletine, oxybutynin, and naproxen, respectively. Methods: Female Sprague-Dawley rats were acutely instrumented with jugular venous, carotid arterial, and bladder cannulas. Needle electrodes were placed directly into the abdominal musculature to measure myoelectrical activity subsequent to repeated phasic urinary bladder distension (60 mmHg for 20 sec in 3 min intervals) under 1% isoflurane. Drugs were administered by i.v. bolus injection 2 min prior to distension. Results: The analgesics morphine (ID50 0.69 mg/kg), U50,488 (1.34 mg/kg), and mexiletine (2.60 mg/kg) significantly inhibited the visceromotor reflex response to noxious urinary bladder distension. Oxybutynin also attenuated reflex responses to noxious urinary bladder distension to 41% of the maximal pressor response and 32% of the control visceromotor reflex response (3.01 and 5.05 mg/kg), respectively, indicating a role of muscarinic receptors in bladder nociception. Naproxen did not attenuate the pressor response, but moderately inhibited visceromotor reflex to 45% of control at 30 mg/kg (P < 0.05). Conclusions: Current results using the rat urinary bladder distension model are consistent with previous research demonstrating a role of the analgesics (morphine, U50,488, and mexiletine) in the inhibition of visceral nociceptive transmission. The utility of the reflex responses to urinary bladder distension may provide a method useful to examine mechanisms which target the bladder sensory pathway.
MeSH term(s)	3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/pharmacology ; Analgesics/pharmacology ; Analgesics, Non-Narcotic ; Analgesics, Opioid/pharmacology ; Animals ; Blood Pressure/drug effects ; Cardiovascular System/drug effects ; Cardiovascular System/innervation ; Cyclooxygenase Inhibitors/pharmacology ; Dose-Response Relationship, Drug ; Female ; Mandelic Acids/pharmacology ; Mexiletine/pharmacology ; Models, Animal ; Morphine/pharmacology ; Muscarinic Antagonists/pharmacology ; Muscle Contraction/drug effects ; Muscle, Skeletal/drug effects ; Muscle, Skeletal/innervation ; Naproxen/pharmacology ; Nociceptors/drug effects ; Nociceptors/metabolism ; Pressure ; Prostaglandin-Endoperoxide Synthases/metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, Muscarinic/drug effects ; Receptors, Opioid, kappa/drug effects ; Receptors, Opioid, mu/drug effects ; Reflex/drug effects ; Sodium Channel Blockers/pharmacology ; Sodium Channels/drug effects ; Urinary Bladder/drug effects ; Urinary Bladder/enzymology ; Urinary Bladder/innervation ; Urinary Bladder/metabolism
Chemical Substances	Analgesics ; Analgesics, Non-Narcotic ; Analgesics, Opioid ; Cyclooxygenase Inhibitors ; Mandelic Acids ; Muscarinic Antagonists ; Receptors, Muscarinic ; Receptors, Opioid, kappa ; Receptors, Opioid, mu ; Sodium Channel Blockers ; Sodium Channels ; Mexiletine (1U511HHV4Z) ; Naproxen (57Y76R9ATQ) ; 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer (67198-13-4) ; Morphine (76I7G6D29C) ; Prostaglandin-Endoperoxide Synthases (EC 1.14.99.1) ; oxybutynin (K9P6MC7092)
Language	English
Publishing date	2008
Publishing country	United States
Document type	Journal Article
ZDB-ID	604904-7
ISSN	1520-6777 ; 0733-2467
ISSN (online)	1520-6777
ISSN	0733-2467
DOI	10.1002/nau.20469
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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Order via subito

Full text online

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In stock of ZB MED Cologne/Königswinter

Order via subito