61 results on '"Sandra R. Chaplan"'
Search Results
2. Effects of the selective orexin-2 receptor antagonist JNJ-48816274 on sleep initiated in the circadian wake maintenance zone: a randomised trial
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Derk-Jan Dijk, Hana Hassanin, Ciro della Monica, Sandra R. Chaplan, Robin Halter, Jeewaka Mendis, and Victoria L. Revell
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Male ,medicine.drug_class ,Polysomnography ,Placebo ,Non-rapid eye movement sleep ,Article ,Double-Blind Method ,Orexin Receptors ,Sleep Initiation and Maintenance Disorders ,Medicine ,Humans ,Effects of sleep deprivation on cognitive performance ,Circadian rhythm ,Pharmacology ,Orexins ,business.industry ,Antagonist ,Receptor antagonist ,Sleep in non-human animals ,Psychiatry and Mental health ,Anesthesia ,Orexin Receptor Antagonists ,Sleep onset latency ,Circadian rhythms and sleep ,business ,Sleep - Abstract
The effects of orexinergic peptides are diverse and are mediated by orexin-1 and orexin-2 receptors. Antagonists that target both receptors have been shown to promote sleep initiation and maintenance. Here, we investigated the role of the orexin-2 receptor in sleep regulation in a randomised, double-blind, placebo-controlled, three-period crossover clinical trial using two doses (20 and 50 mg) of a highly selective orexin-2 receptor antagonist (2-SORA) (JNJ-48816274). We used a phase advance model of sleep disruption where sleep initiation is scheduled in the circadian wake maintenance zone. We assessed objective and subjective sleep parameters, pharmacokinetic profiles and residual effects on cognitive performance in 18 healthy male participants without sleep disorders. The phase advance model alone (placebo condition) resulted in disruption of sleep at the beginning of the sleep period compared to baseline sleep (scheduled at habitual time). Compared to placebo, both doses of JNJ-48816274 significantly increased total sleep time, REM sleep duration and sleep efficiency, and reduced latency to persistent sleep, sleep onset latency, and REM latency. All night EEG spectral power density for both NREM and REM sleep were unaffected by either dose. Participants reported significantly better quality of sleep and feeling more refreshed upon awakening following JNJ-48816274 compared to placebo. No significant residual effects on objective performance measures were observed and the compound was well tolerated. In conclusion, the selective orexin-2 receptor antagonist JNJ-48816274 rapidly induced sleep when sleep was scheduled earlier in the circadian cycle and improved self-reported sleep quality without impact on waking performance.
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- 2021
3. The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: a randomized clinical trial
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Sandra R. Chaplan, Murray B. Stein, Robin Halter, Alan N. Simmons, Martin P. Paulus, and Victoria B. Risbrough
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Male ,Anxiety ,Placebo ,Amygdala ,Article ,Amidohydrolases ,03 medical and health sciences ,0302 clinical medicine ,Fatty acid amide hydrolase ,medicine ,Humans ,Fear conditioning ,Pharmacology ,business.industry ,Extinction (psychology) ,Fear ,Anticipation ,Anxiety Disorders ,Magnetic Resonance Imaging ,030227 psychiatry ,Psychiatry and Mental health ,medicine.anatomical_structure ,medicine.symptom ,business ,Insula ,Neuroscience ,030217 neurology & neurosurgery ,psychological phenomena and processes - Abstract
Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), prolongs the regulatory effects of endocannabinoids and reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. However, the neural systems underlying this modulation are poorly understood. A single site, randomized, double-blind, placebo-controlled, parallel study was conducted with 43 subjects assigned to receive once daily dosing of either placebo (n = 21) or JNJ-42165279 (100 mg) (n = 22) for 4 consecutive days. Pharmacodynamic effects were assessed on the last day of dosing and included evaluation of brain activation patterns using BOLD fMRI during an (1) emotion face-processing task, (2) inspiratory breathing load task, and (3) fear conditioning and extinction task. JNJ-42165279 attenuated activation in the amygdala, bilateral anterior cingulate, and bilateral insula during the emotion face-processing task consistent with effects previously observed with anxiolytic agents. Higher levels of anandamide were associated with greater attenuation in bilateral anterior cingulate and left insula. JNJ-42165279 increased the activation during anticipation of an aversive interoceptive event in the anterior cingulate and bilateral anterior insula and right inferior frontal cortex. JNJ-42165279 did not affect fear conditioning or within-session extinction learning as evidenced by a lack of differences on a subjective and neural circuit level. Taken together, these results support the hypothesis that JNJ-42165279 at this dose shares some effects with existing anxiolytic agents in dampening response to emotional stimuli but not responses to conditioned fear.
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- 2020
4. Selective inhibition of peripheral cathepsin S reverses tactile allodynia following peripheral nerve injury in mouse
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Karlsson Lars, Siquan Sun, Michael K. Ameriks, Steven Nguyen, Karen Ngo, Jian Zhu, Cheryl A. Grice, Robin L. Thurmond, Sandra R. Chaplan, Hui Cai, William A. Eckert, John J. M. Wiener, James P. Edwards, and Wai-Ping Fung-Leung
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0301 basic medicine ,Male ,SNi ,Hot Temperature ,T-Lymphocytes ,Analgesic ,Pharmacology ,Cell Line ,03 medical and health sciences ,0302 clinical medicine ,Peripheral Nerve Injuries ,medicine ,Tetanus Toxoid ,Animals ,Humans ,Protease Inhibitors ,Cathepsin S ,Mice, Knockout ,Analgesics ,CATS ,business.industry ,Brain ,Nerve injury ,Immunoglobulin E ,Cathepsins ,Sciatic Nerve ,Mice, Inbred C57BL ,030104 developmental biology ,Allodynia ,Hyperalgesia ,Touch ,Immunoglobulin G ,Peripheral nerve injury ,Neuropathic pain ,Cytokines ,Neuralgia ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Immunosuppressive Agents - Abstract
Cathepsin S (CatS) is a cysteine protease found in lysosomes of hematopoietic and microglial cells and in secreted form in the extracellular space. While CatS has been shown to contribute significantly to neuropathic pain, the precise mechanisms remain unclear. In this report, we describe JNJ-39641160, a novel non-covalent, potent, selective and orally-available CatS inhibitor that is peripherally restricted (non-CNS penetrant) and may represent an innovative class of immunosuppressive and analgesic compounds and tools useful toward investigating peripheral mechanisms of CatS in neuropathic pain. In C57BL/6 mice, JNJ-39641160 dose-dependently blocked the proteolysis of the invariant chain, and inhibited both T-cell activation and antibody production to a vaccine antigen. In the spared nerve injury (SNI) model of chronic neuropathic pain, in which T-cell activation has previously been demonstrated to be a prerequisite for the development of pain hypersensitivity, JNJ-39641160 fully reversed tactile allodynia in wild-type mice but was completely ineffective in the same model in CatS knockout mice (which exhibited a delayed onset in allodynia). By contrast, in the acute mild thermal injury (MTI) model, JNJ-39641160 only weakly attenuated allodynia at the highest dose tested. These findings support the hypothesis that blockade of peripheral CatS alone is sufficient to fully reverse allodynia following peripheral nerve injury and suggest that the mechanism of action likely involves interruption of T-cell activation and peripheral cytokine release. In addition, they provide important insights toward the development of selective CatS inhibitors for the treatment of neuropathic pain in humans.
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- 2020
5. The discovery and preclinical characterization of 6-chloro- N -(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists
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Alec D. Lebsack, Alan D. Wickenden, Sandra R. Chaplan, Qi Wang, Jason C. Rech, Love Christopher John, William A. Eckert, J. Guy Breitenbucher, Ludwig Paul Cooymans, Leenaerts Joseph Elisabeth, Anindya Bhattacharya, Bryan James Branstetter, and Hong Ao
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0301 basic medicine ,Purinergic P2X Receptor Antagonists ,medicine.drug_class ,Stereochemistry ,Interleukin-1beta ,Clinical Biochemistry ,Analgesic ,Pharmaceutical Science ,Carboxamide ,Tactile Allodynia ,Biochemistry ,Mice ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Molecular Biology ,Whole blood ,Trifluoromethyl ,Chemistry ,Organic Chemistry ,Quinoline ,030104 developmental biology ,Quinolines ,Molecular Medicine ,030217 neurology & neurosurgery ,Ex vivo ,Paw edema - Abstract
The synthesis, SAR and preclinical characterization of a series of 6-chloro- N -(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca 2+ flux and whole blood IL-1β P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1β release in a mouse ex vivo model with a 50 mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects.
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- 2016
6. Characterization of JNJ-42847922, a Selective Orexin-2 Receptor Antagonist, as a Clinical Candidate for the Treatment of Insomnia
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James R Shoblock, Sandra R. Chaplan, Anthony Ndifor, Steven W. Sutton, Nicholas I. Carruthers, Robin Halter, Michele C. Rizzolio, Ian Fraser, Tatiana Koudriakova, Pascal Bonaventure, Sujin Yun, Leah Aluisio, Christine Dugovic, Zuleima Aguilar, Jonathan Shelton, Brian Lord, Natalie Welty, Timothy W. Lovenberg, Michael A. Letavic, and Diane Nepomuceno
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Male ,medicine.medical_specialty ,Zolpidem ,Pyridines ,medicine.drug_class ,Dopamine ,Sleep, REM ,CHO Cells ,Pharmacology ,Non-rapid eye movement sleep ,Cell Line ,Rats, Sprague-Dawley ,Hypnotic ,Mice ,Cricetulus ,Sleep Initiation and Maintenance Disorders ,Internal medicine ,medicine ,Insomnia ,Animals ,Humans ,Hypnotics and Sedatives ,Mice, Knockout ,Binding Sites ,business.industry ,Brain ,Sleep in non-human animals ,Rats ,HEK293 Cells ,Endocrinology ,Sedative ,Molecular Medicine ,Orexin Receptor Antagonists ,Sleep Stages ,medicine.symptom ,Sleep onset ,Sleep ,business ,Somnolence ,medicine.drug - Abstract
Dual orexin receptor antagonists have been shown to promote sleep in various species, including humans. Emerging research indicates that selective orexin-2 receptor (OX2R) antagonists may offer specificity and a more adequate sleep profile by preserving normal sleep architecture. Here, we characterized JNJ-42847922 ([5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone), a high-affinity/potent OX2R antagonist. JNJ-42847922 had an approximate 2-log selectivity ratio versus the human orexin-1 receptor. Ex vivo receptor binding studies demonstrated that JNJ-42847922 quickly occupied OX2R binding sites in the rat brain after oral administration and rapidly cleared from the brain. In rats, single oral administration of JNJ-42847922 (3-30 mg/kg) during the light phase dose dependently reduced the latency to non-rapid eye movement (NREM) sleep and prolonged NREM sleep time in the first 2 hours, whereas REM sleep was minimally affected. The reduced sleep onset and increased sleep duration were maintained upon 7-day repeated dosing (30 mg/kg) with JNJ-42847922, then all sleep parameters returned to baseline levels following discontinuation. Although the compound promoted sleep in wild-type mice, it had no effect in OX2R knockout mice, consistent with a specific OX2R-mediated sleep response. JNJ-42847922 did not increase dopamine release in rat nucleus accumbens or produce place preference in mice after subchronic conditioning, indicating that the compound lacks intrinsic motivational properties in contrast to zolpidem. In a single ascending dose study conducted in healthy subjects, JNJ-42847922 increased somnolence and displayed a favorable pharmacokinetic and safety profile for a sedative/hypnotic, thus emerging as a promising candidate for further clinical development for the treatment of insomnia.
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- 2015
7. 1-Aryl-2-((6-aryl)pyrimidin-4-yl)amino)ethanols as competitive inhibitors of fatty acid amide hydrolase
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Sandra R. Chaplan, Brian Scott, Michele C. Rizzolio, Joan Pierce, Natalie A. Hawryluk, Mark Seierstad, Leon Chang, J. Guy Breitenbucher, Michelle L. Wennerholm, Mark J. Karbarz, Richard Apodaca, Sandy J. Wilson, John M. Keith, James A. Palmer, Allison Chambers, Michael Webb, and Lin Luo
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Stereochemistry ,education ,Clinical Biochemistry ,Rat model ,Pharmaceutical Science ,Plasma protein binding ,Biochemistry ,Amidohydrolases ,Structure-Activity Relationship ,chemistry.chemical_compound ,Fatty acid amide hydrolase ,Catalytic Domain ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Enzyme Inhibitors ,Binding site ,Molecular Biology ,chemistry.chemical_classification ,Analgesics ,Binding Sites ,Aryl ,Organic Chemistry ,Target engagement ,Brain ,Amino Alcohols ,humanities ,Rats ,Molecular Docking Simulation ,Disease Models, Animal ,Pyrimidines ,Enzyme ,chemistry ,Neuralgia ,Molecular Medicine ,Half-Life ,Protein Binding - Abstract
A series of 1-aryl-2-(((6-aryl)pyrimidin-4-yl)amino)ethanols have been found to be competitive inhibitors of fatty acid amide hydrolase (FAAH). One member of this class, JNJ-40413269, was found to have excellent pharmacokinetic properties, demonstrated robust central target engagement, and was efficacious in a rat model of neuropathic pain.
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- 2014
8. Heteroarylureas with spirocyclic diamine cores as inhibitors of fatty acid amide hydrolase
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Raymond Rynberg, Sandy J. Wilson, William M. Jones, Michele C. Rizzolio, Mark Seierstad, Lin Luo, John M. Keith, Michelle Wennerholm, Joan Pierce, Michael Webb, Sean Brown, James A. Palmer, Sandra R. Chaplan, Mark J. Karbarz, Brian Scott, Leon Chang, and J. Guy Breitenbucher
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Stereochemistry ,Clinical Biochemistry ,Administration, Oral ,Pharmaceutical Science ,Diamines ,Biochemistry ,Amidohydrolases ,chemistry.chemical_compound ,Heterocyclic Compounds ,Fatty acid amide hydrolase ,Diamine ,Drug Discovery ,Hydrolase ,Animals ,Urea ,Ethanolamide ,Spiro Compounds ,Molecular Biology ,chemistry.chemical_classification ,Molecular Structure ,Organic Chemistry ,Brain ,Fatty acid ,Serine hydrolase ,Anandamide ,Endocannabinoid system ,Rats ,Enzyme Activation ,chemistry ,Cyclization ,Azetidines ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) - Abstract
A series of mechanism based heteroaryl urea fatty acid amide hydrolase (FAAH) inhibitors with spirocyclic diamine cores is described. A potent member of this class, (37), was found to inhibit FAAH centrally, elevate the brain levels of three fatty acid ethanolamides [FAAs: anandamide (AEA), oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA)], and was moderately efficacious in a rat model of neuropathic pain.
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- 2014
9. The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors
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Sandy J. Wilson, Brian Scott, Mark S. Tichenor, Michele C. Rizzolio, Sandra R. Chaplan, Michael Webb, James A. Palmer, J. Guy Breitenbucher, Michelle L. Wennerholm, Raymond Rynberg, Mark Seierstad, Wei Xiao, Mark J. Karbarz, Richard Apodaca, John M. Keith, William M. Jones, and Joan Pierce
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0301 basic medicine ,Stereochemistry ,Clinical Biochemistry ,Central nervous system ,Pharmaceutical Science ,Blood–brain barrier ,Biochemistry ,Amidohydrolases ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,0302 clinical medicine ,Pharmacokinetics ,Fatty acid amide hydrolase ,Drug Discovery ,medicine ,Humans ,Urea ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Target engagement ,Brain ,Penetration (firestop) ,030104 developmental biology ,medicine.anatomical_structure ,Enzyme ,chemistry ,Molecular Medicine ,030217 neurology & neurosurgery - Abstract
The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.
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- 2016
10. Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate
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Michael Webb, Sean Brown, Sandy J. Wilson, John M. Keith, Michelle Wennerholm, James A. Palmer, Lin Luo, Mark S. Tichenor, Wei Xiao, Michele C. Rizzolio, Brian Scott, Leon Chang, J. Guy Breitenbucher, William M. Jones, Sandra R. Chaplan, Raymond Rynberg, Joan Pierce, Rich Apodaca, Mark Seierstad, and Mark J. Karbarz
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chemistry.chemical_classification ,Aryl ,Organic Chemistry ,Fatty acid ,Anandamide ,Pharmacology ,Biochemistry ,chemistry.chemical_compound ,Enzyme ,chemistry ,Covalent bond ,Fatty acid amide hydrolase ,Drug Discovery ,Urea ,Ethanolamide ,lipids (amino acids, peptides, and proteins) - Abstract
A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.
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- 2012
11. Characterization of 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729209) as a novel TRPV1 antagonist
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Michael P. Maher, Sandra R. Chaplan, Jing Liu, Jason C. Rech, Brian Scott, William A. Eckert, Bryan James Branstetter, Hong Ao, Anne E. Fitzgerald, Yi Liu, Nyantsz Wu, Michele C. Rizzolio, Anindya Bhattacharya, Jamie M. Freedman, Alec D. Lebsack, Nadia Swanson, J. Guy Breitenbucher, Dong H. Li, Alan D. Wickenden, Kia Sepassi, and Mena Kansagara
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Male ,Stereochemistry ,Guinea Pigs ,Analgesic ,TRPV1 ,TRPV Cation Channels ,Pharmacology ,Body Temperature ,Cell Line ,Mice ,chemistry.chemical_compound ,Dogs ,Pharmacokinetics ,medicine ,Animals ,Humans ,Volume of distribution ,Clinical Trials as Topic ,Antagonist ,Hypothermia ,Rats ,Bioavailability ,Thiazoles ,Pyrimidines ,Cough ,chemistry ,Hyperalgesia ,Capsaicin ,Female ,lipids (amino acids, peptides, and proteins) ,Hypotension ,medicine.symptom - Abstract
As an integrator of multiple nociceptive and/or inflammatory stimuli, TRPV1 is an attractive therapeutic target for the treatment of various painful disorders. Several TRPV1 antagonists have been advanced into clinical trials and the initial observations suggest that TRPV1 antagonism may be associated with mild hyperthermia and thermal insensitivity in man. However, no clinical efficacy studies have been described to date, making an assessment of risk:benefit impossible. Furthermore, it is not clear whether these early observations are representative of all TRPV1 antagonists and whether additional clinical studies with novel TRPV1 antagonists are required in order to understand optimal compound characteristics. In the present study we describe 2-(2,6-dichloro-benzyl)-thiazolo[5,4-d]pyrimidin-7-yl]-(4-trifluoromethyl-phenyl)-amine (JNJ-39729309) as a novel, TRPV1 antagonist. JNJ-39729209 displaced tritiated resiniferotoxin binding to TRPV1 and prevented TRPV1 activation by capsaicin, protons and heat. In-vivo, JNJ-39729209 blocked capsaicin-induced hypotension, induced a mild hyperthermia and inhibited capsaicin-induced hypothermia in a dose dependent manner. JNJ-39729209 showed significant efficacy against carrageenan- and CFA-evoked thermal hyperalgesia and exhibited significant anti-tussive activity in a guinea-pig model of capsaicin-induced cough. In pharmacokinetic studies, JNJ-39729209 was found to have low clearance, a moderate volume of distribution, good oral bioavailability and was brain penetrant. On the basis of these findings, JNJ-39729209 represents a structurally novel TRPV1 antagonist with potential for clinical development. The advancement of JNJ-39729209 into human clinical trials could be useful in further understanding the analgesic potential of TRPV1 antagonists.
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- 2011
12. 1,2-Diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines as TRPV1 antagonists with improved properties
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Michelle Herrmann, Brett D. Allison, Alec D. Lebsack, Nadia Swanson, Hong Ao, Johnathan C. Buma, Brian Scott, J. Guy Breitenbucher, Jason C. Rech, Bryan James Branstetter, Alan D. Wickenden, Raymond Rynberg, Michael P. Maher, Sandra R. Chaplan, Anindya Bhattacharya, Lin Luo, Qi Wang, Michele C. Rizzolio, Natalie A. Hawryluk, Jamie M. Freedman, and Jeffrey E. Merit
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Stereochemistry ,Clinical Biochemistry ,TRPV Cation Channels ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Medicinal chemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pharmacokinetics ,Drug Discovery ,Animals ,Humans ,Azepine ,Molecular Biology ,Aqueous solution ,Dose-Response Relationship, Drug ,Organic Chemistry ,Antagonist ,Biological activity ,Azepines ,Hydrogen-Ion Concentration ,Rats ,Bioavailability ,Solubility ,chemistry ,Hyperalgesia ,Molecular Medicine ,Lead compound - Abstract
Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure–activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 = >237 μg/mL and SIF = 11 μg/mL) was significantly improved over compound 1 (pH 2 = 5 μg/mL and SIF = 0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL = 0.7 L/kg/h) compared to compound 1 (CL = 3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
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- 2010
13. Discovery and synthesis of 6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepines as novel TRPV1 antagonists
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Qi Wang, J. Guy Breitenbucher, Hong Ao, Michael D. Hack, Bryan James Branstetter, Alan D. Wickenden, Jamie M. Freedman, Alec D. Lebsack, Nadia Swanson, Michael P. Maher, Sandra R. Chaplan, Natalie A. Hawryluk, Jeffrey E. Merit, Brian Scott, and Anindya Bhattacharya
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Chemistry ,Stereochemistry ,organic chemicals ,Organic Chemistry ,Clinical Biochemistry ,TRPV1 ,TRPV Cation Channels ,Pharmaceutical Science ,Azepines ,Biochemistry ,Chemical synthesis ,In vitro ,Rats ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,polycyclic compounds ,Animals ,Molecular Medicine ,Potency ,heterocyclic compounds ,Molecular Biology - Abstract
Utilization of a tetrahydro-pyrimdoazepine core as a bioisosteric replacement for a piperazine-urea resulted in the discovery a novel series of potent antagonists of TRPV1. The tetrahydro-pyrimdoazepines have been identified as having good in vitro and in vivo potency and acceptable physical properties.
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- 2010
14. HCN Channels as Targets for Drug Discovery
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Adrienne E. Dubin, Michael P. Maher, Sandra R. Chaplan, Nyantsz Wu, Hongqing Guo, and Alan D. Wickenden
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Membrane potential ,Analgesics ,Potassium Channels ,biology ,Drug discovery ,Chemistry ,Organic Chemistry ,Drug Evaluation, Preclinical ,Cyclic Nucleotide-Gated Cation Channels ,Sensory system ,General Medicine ,Hyperpolarization (biology) ,Pharmacology ,Pain sensation ,Analgesic agents ,Computer Science Applications ,Transmembrane domain ,Drug Delivery Systems ,Drug Discovery ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,HCN channel ,biology.protein ,Animals ,Humans ,Neuroscience - Abstract
Hyperpolarization- and Cyclic Nucleotide-gated (HCN) channels are a family of six transmembrane domain, single pore-loop, hyperpolarization activated, non-selective cation channels. The HCN family consists of four members (HCN1-4). HCN channels represent the molecular correlates of I(h) (also known as 'funny' I(f) and 'queer' I(q)), a hyperpolarization-activated current best known for its role in controlling heart rate and in the regulation of neuronal resting membrane potential and excitability. A significant body of molecular and pharmacological evidence is now emerging to support a role for these channels in the function of sensory neurons and pain sensation, particularly pain associated with nerve or tissue injury. As such, HCN channels may represent valid targets for novel analgesic agents. This evidence will be reviewed in this article. We will then summarize our efforts to develop and validate methods for screening for novel HCN channel blockers.
- Published
- 2009
15. Identification and synthesis of 2,7-diamino-thiazolo[5,4-d]pyrimidine derivatives as TRPV1 antagonists
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Matthew L. Peterson, Bryan James Branstetter, Lin Luo, Alec D. Lebsack, Michael P. Maher, Sandra R. Chaplan, Michele C. Rizzolio, Anindya Bhattacharya, J. Guy Breitenbucher, Nadia Nasser, Hong Ao, Wei Xiao, Michael D. Hack, Mena Kansagara, Brian Scott, Alan D. Wickenden, and Raymond Rynberg
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Pyrimidine ,Stereochemistry ,Clinical Biochemistry ,Treatment outcome ,TRPV Cation Channels ,TRPV1 ,Administration, Oral ,Pharmaceutical Science ,Thermal Hyperalgesia ,Biochemistry ,Structure-Activity Relationship ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Animals ,Structure–activity relationship ,Molecular Biology ,Organic Chemistry ,Rats ,Thiazoles ,Pyrimidines ,Treatment Outcome ,chemistry ,Hyperalgesia ,Molecular Medicine ,medicine.symptom - Abstract
We have identified and synthesized a series of 2,7-diamino-thiazolo[5,4-d]pyrimidines as TRPV1 antagonists. An exploration of the structure-activity relationships at the 2-, 5-, and 7-positions of the thiazolo[5,4-d]pyrimidine led to the identification of several potent TRPV1 antagonists, including 3, 29, 51, and 57. Compound 3 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia with an ED(50)=0.5mg/kg in rats.
- Published
- 2009
16. Biochemical and Biological Properties of 4-(3-phenyl-[1,2,4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a Mechanism-Based Inhibitor of Fatty Acid Amide Hydrolase
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James Guy Breitenbucher, Michelle Wennerholm, Sean Brown, James A. Palmer, John M. Keith, Chui-Se Tham, Jiejun Wu, Sandy J. Wilson, Michael Webb, Mark J. Karbarz, Lin Luo, Sandra R. Chaplan, Brian Scott, Leon Chang, and Richard Apodaca
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Male ,Hot Temperature ,Oleic Acids ,Carrageenan ,Esterase ,Piperazines ,Rats, Sprague-Dawley ,Mice ,chemistry.chemical_compound ,Fatty acid amide hydrolase ,Medicine ,Ethanolamide ,Enzyme Inhibitors ,Pain Measurement ,Mice, Knockout ,chemistry.chemical_classification ,Analgesics ,Hydrolysis ,Brain ,Biological activity ,Anandamide ,Endocannabinoid system ,Recombinant Proteins ,Isoenzymes ,Biochemistry ,Ethanolamines ,lipids (amino acids, peptides, and proteins) ,Esterase inhibitor ,Pain Threshold ,Polyunsaturated Alkamides ,Pain ,Arachidonic Acids ,Palmitic Acids ,Amidohydrolases ,Thiadiazoles ,Reaction Time ,Animals ,Humans ,Dose-Response Relationship, Drug ,business.industry ,Amides ,Rats ,Mice, Inbred C57BL ,Disease Models, Animal ,Kinetics ,Anesthesiology and Pain Medicine ,Enzyme ,chemistry ,Neuralgia ,business ,Endocannabinoids - Abstract
Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme within the amidase-signature family. It catalyzes the hydrolysis of several endogenous biologically active lipids, including anandamide (arachidonoyl ethanolamide), oleoyl ethanolamide, and palmitoyl ethanolamide. These endogenous FAAH substrates have been shown to be involved in a variety of physiological and pathological processes, including synaptic regulation, regulation of sleep and feeding, locomotor activity, pain and inflammation. Here we describe the biochemical and biological properties of a potent and selective FAAH inhibitor, 4-(3-phenyl-[1,2,4]thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide (JNJ-1661010). The time-dependence of apparent IC(50) values at rat and human recombinant FAAH, dialysis and mass spectrometry data indicate that the acyl piperazinyl fragment of JNJ-1661010 forms a covalent bond with the enzyme. This bond is slowly hydrolyzed, with release of the piperazinyl fragment and recovery of enzyme activity. The lack of inhibition observed in a rat liver esterase assay suggests that JNJ-1661010 is not a general esterase inhibitor. JNJ-1661010 is >100-fold preferentially selective for FAAH-1 when compared to FAAH-2. JNJ-1661010 dose-dependently increases arachidonoyl ethanolamide, oleoyl ethanolamide, and palmitoyl ethanolamide in the rat brain. The compound attenuates tactile allodynia in the rat mild thermal injury model of acute tissue damage and in the rat spinal nerve ligation (Chung) model of neuropathic pain. JNJ-1661010 also diminishes thermal hyperalgesia in the inflammatory rat carrageenan paw model. These data suggest that FAAH inhibitors with modes of action similar to JNJ-1661010 may be useful clinically as broad-spectrum analgesics.
- Published
- 2009
17. Thiadiazolopiperazinyl ureas as inhibitors of fatty acid amide hydrolase
- Author
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James A. Palmer, Michael Webb, Michelle Wennerholm, Pattabiraman Kanaka, Mark J. Karbarz, Sandy J. Wilson, Sandra R. Chaplan, Chui-Se Tham, Lin Luo, Brian Scott, Mark Seierstad, J. Guy Breitenbucher, Wei Xiao, Jiejun Wu, Richard Apodaca, John M. Keith, and Sean Brown
- Subjects
Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Piperazines ,Amidohydrolases ,Amidase ,Mice ,chemistry.chemical_compound ,Fatty acid amide hydrolase ,Thiadiazoles ,Drug Discovery ,Animals ,Urea ,Molecular Biology ,Mice, Knockout ,chemistry.chemical_classification ,Aryl ,Organic Chemistry ,Anandamide ,Piperazine ,Enzyme ,chemistry ,Covalent bond ,Molecular Medicine - Abstract
A series of thiadiazolopiperazinyl aryl urea fatty acid amide hydrolase (FAAH) inhibitors is described. The molecules were found to inhibit the enzyme by acting as mechanism-based substrates, forming a covalent bond with Ser241. SAR and PK properties are presented.
- Published
- 2008
18. Novel ketooxazole based inhibitors of fatty acid amide hydrolase (FAAH)
- Author
-
Sean Brown, Leon Chang, J. Guy Breitenbucher, Brian Scott, Mark Seierstad, Dan Pippel, Michael Webb, Matt Epperson, Amy K. Timmons, Rich Apodaca, and Sandra R. Chaplan
- Subjects
Pyridines ,medicine.medical_treatment ,Clinical Biochemistry ,Pain ,Pharmaceutical Science ,Biochemistry ,Amidohydrolases ,Amidase ,Structure-Activity Relationship ,Fatty acid amide hydrolase ,Drug Discovery ,medicine ,Animals ,Humans ,Structure–activity relationship ,Oxazoles ,Molecular Biology ,Pain Measurement ,Binding Sites ,biology ,Chemistry ,Organic Chemistry ,Biological activity ,Endocannabinoid system ,Rats ,Spinal Nerves ,Enzyme inhibitor ,Neuropathic pain ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,psychological phenomena and processes - Abstract
Efforts to improve the properties of the well studied ketooxazole FAAH inhibitor OL-135 resulted in the discovery of a novel propylpiperidine series of FAAH inhibitors that has a modular design and superior properties to OL-135. The efficacy of one of these compounds was demonstrated in a rat spinal nerve ligation model of neuropathic pain in rats.
- Published
- 2008
19. Activation of TRPA1 by Farnesyl Thiosalicylic Acid
- Author
-
Nadia Nasser, Hong Ao, Tue G. Banke, J. Guy Breitenbucher, Nyantsz Wu, Michael P. Maher, Sandra R. Chaplan, and Alan D. Wickenden
- Subjects
Male ,Agonist ,Thiosalicylic acid ,Patch-Clamp Techniques ,medicine.drug_class ,Stereochemistry ,chemistry.chemical_element ,Nerve Tissue Proteins ,CHO Cells ,Calcium ,Transfection ,Fluorescence ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Cricetulus ,Dogs ,Transient Receptor Potential Channels ,Isothiocyanates ,Cricetinae ,Ganglia, Spinal ,medicine ,Animals ,Humans ,TRPA1 Cation Channel ,Cells, Cultured ,Pharmacology ,Voltage-dependent calcium channel ,food and beverages ,Farnesol ,Ruthenium Red ,Salicylates ,Rats ,Electrophysiology ,chemistry ,Mechanism of action ,Disulfiram ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Calcium Channels ,medicine.symptom ,Thioacetic acid ,Ion Channel Gating ,psychological phenomena and processes ,medicine.drug - Abstract
The nonselective cation channel TRPA1 (ANKTM1, p120) is a potential mediator of pain, and selective pharmacological modulation of this channel may be analgesic. Although several TRPA1 activators exist, these tend to be either reactive or of low potency and/or selectivity. The aim of the present study, therefore, was to identify novel TRPA1 agonists. Using a combination of calcium fluorescent assays and whole-cell electrophysiology, we discovered several compounds that possess potent, selective TRPA1-activating activity, including several lipid compounds (farnesyl thiosalicylic acid, farnesyl thioacetic acid, 15-deoxy-Delta(12,14)-prostaglandin J(2), and 5,8,11,14-eicosatetraynoic acid), and two marketed drugs: disulfiram (Antabuse; a compound used in the treatment of alcohol abuse) and the antifungal agent chlordantoin. Farnesyl thiosalicylic acid activates the channel in excised patches and in the absence of calcium. Furthermore, using a quadruple TRPA1 mutant, we show that the mechanism of action of farnesyl thiosalicylic acid differs from that of the reactive electrophilic reagent allylisothiocyanate. As a TRPA1 agonist with a potentially novel mechanism of action, farnesyl thiosalicylic acid may be useful in the study of TRPA1 channels.
- Published
- 2008
20. Pharmacology and Antitussive Efficacy of 4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic Acid (5-Trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), a Transient Receptor Potential Vanilloid 1 Antagonist in Guinea Pigs
- Author
-
Hong Ao, Nigel P. Shankley, Brian Scott, Nadia Nasser, Alan D. Wickenden, Adrienne E. Dubin, Michael P. Maher, Sandra R. Chaplan, Anindya Bhattacharya, and Swanson Devin M
- Subjects
Male ,Cough reflex ,Guinea Pigs ,TRPV1 ,Aminopyridines ,TRPV Cation Channels ,CHO Cells ,Pharmacology ,Piperazines ,Guinea pig ,chemistry.chemical_compound ,Cricetulus ,Pharmacokinetics ,Cricetinae ,Animals ,Patch clamp ,Dose-Response Relationship, Drug ,Chemistry ,Antagonist ,Antitussive Agents ,Cough ,Capsaicin ,Molecular Medicine ,Female ,Antagonism - Abstract
Transient receptor potential vanilloid 1 (TRPV1) plays an integral role in modulating the cough reflex, and it is an attractive antitussive drug target. The purpose of this study was to characterize a TRPV1 antagonist, 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid (5-trifluoromethyl-pyridin-2-yl)-amide (JNJ17203212), against the guinea pig TRPV1 receptor in vitro followed by a proof-of-principle study in an acid-induced model of cough. The affinity of JNJ17203212 for the recombinant guinea pig TRPV1 receptor was estimated by radioligand binding, and it was functionally characterized by antagonism of low-pH and capsaicin-induced activation of the ion channel (fluorometric imaging plate reader and electrophysiology). The nature of antagonism was further tested against the native channel in isolated guinea pig tracheal rings. Following pharmacokinetic characterization of JNJ17203212 in guinea pigs, pharmacodynamic and efficacy studies were undertaken to establish the antitussive efficacy of the TRPV1 antagonist. The pK(i) of JNJ17203212 for recombinant guinea pig TRPV1 was 7.14 +/- 0.06. JNJ17203212 inhibited both pH (pIC(50) of 7.23 +/- 0.05) and capsaicin (pIC(50) of 6.32 +/- 0.06)-induced channel activation. In whole-cell patch clamp, the pIC(50) for inhibition of guinea pig TRPV1 was 7.3 +/- 0.01. JNJ17203212 demonstrated surmountable antagonism in isolated trachea, with a pK(B) value of 6.2 +/- 0.1. Intraperitoneal administration of 20 mg/kg JNJ17203212 achieved a maximal plasma exposure of 8.0 +/- 0.4 microM, and it attenuated capsaicin evoked coughs with similar efficacy to codeine (25 mg/kg). Last, JNJ17203212 dose-dependently produced antitussive efficacy in citric acid-induced experimental cough in guinea pigs. Our data provide preclinical support for developing TRPV1 antagonists for the treatment of cough.
- Published
- 2007
21. Antihistamines and itch
- Author
-
Robin L, Thurmond, Kayvan, Kazerouni, Sandra R, Chaplan, and Andrew J, Greenspan
- Subjects
Pruritus ,Histamine Antagonists ,Animals ,Humans ,Receptors, Histamine ,Histamine - Abstract
Histamine is one of the best-characterized pruritogens in humans. It is known to play a role in pruritus associated with urticaria as well as ocular and nasal allergic reactions. Histamine mediates its effect via four receptors. Antihistamines that block the activation of the histamine H₁receptor, H₁R, have been shown to be effective therapeutics for the treatment of pruritus associated with urticaria, allergic rhinitis, and allergic conjunctivitis. However, their efficacy in other pruritic diseases such as atopic dermatitis and psoriasis is limited. The other histamine receptors may also play a role in pruritus, with the exception of the histamine H₂receptor, H₂R. Preclinical evidence indicates that local antagonism of the histamine H₃receptor, H₃R, can induce scratching perhaps via blocking inhibitory neuronal signals. The histamine H₄receptor, H₄R, has received a significant amount of attention as to its role in mediating pruritic signals. Indeed, it has now been shown that a selective H₄R antagonist can inhibit histamine-induced itch in humans. This clinical result, in conjunction with efficacy in various preclinical pruritus models, points to the therapeutic potential of H₄R antagonists for the treatment of pruritus not controlled by antihistamines that target the H₁R.
- Published
- 2015
22. Antihistamines and Itch
- Author
-
Robin L. Thurmond, Kayvan Kazerouni, Andrew Greenspan, and Sandra R. Chaplan
- Subjects
business.industry ,Histamine H1 receptor ,medicine.disease ,Allergic conjunctivitis ,chemistry.chemical_compound ,Histamine receptor ,chemistry ,Histamine H2 receptor ,Immunology ,medicine ,Histamine H4 receptor ,Histamine H3 receptor ,skin and connective tissue diseases ,business ,Receptor ,Histamine - Abstract
Histamine is one of the best-characterized pruritogens in humans. It is known to play a role in pruritus associated with urticaria as well as ocular and nasal allergic reactions. Histamine mediates its effect via four receptors. Antihistamines that block the activation of the histamine H1 receptor, H1R, have been shown to be effective therapeutics for the treatment of pruritus associated with urticaria, allergic rhinitis, and allergic conjunctivitis. However, their efficacy in other pruritic diseases such as atopic dermatitis and psoriasis is limited. The other histamine receptors may also play a role in pruritus, with the exception of the histamine H2 receptor, H2R. Preclinical evidence indicates that local antagonism of the histamine H3 receptor, H3R, can induce scratching perhaps via blocking inhibitory neuronal signals. The histamine H4 receptor, H4R, has received a significant amount of attention as to its role in mediating pruritic signals. Indeed, it has now been shown that a selective H4R antagonist can inhibit histamine-induced itch in humans. This clinical result, in conjunction with efficacy in various preclinical pruritus models, points to the therapeutic potential of H4R antagonists for the treatment of pruritus not controlled by antihistamines that target the H1R.
- Published
- 2015
23. Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms
- Author
-
James A. Palmer, Sandy J. Wilson, Ann J. Barbier, Steven W. Sutton, Sandra R. Chaplan, Leon Chang, James Guy Breitenbucher, Michael Webb, and Lin Luo
- Subjects
Pharmacology ,Biochemistry ,Chemistry ,Fatty acid amide hydrolase - Published
- 2006
24. Neuronal Hyperpolarization-Activated Pacemaker Channels Drive Neuropathic Pain
- Author
-
Alexander A. Velumian, Adrienne E. Dubin, Lin Luo, Sandra R. Chaplan, Matthew P. Butler, Doo Hyun Lee, Chester Kuei, Sean Brown, Changlu Liu, and Hongqing Guo
- Subjects
Male ,Potassium Channels ,Action Potentials ,Cyclic Nucleotide-Gated Cation Channels ,Nerve Tissue Proteins ,Ion Channels ,Cell Line ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Ganglia, Spinal ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,HCN channel ,Animals ,Humans ,Medicine ,RNA, Messenger ,ARTICLE ,Cells, Cultured ,Nerve ligation ,Neurons ,biology ,business.industry ,General Neuroscience ,Cell Membrane ,Electric Conductivity ,Hyperpolarization (biology) ,Nerve injury ,Rats ,Peripheral ,Blockade ,Kinetics ,Pyrimidines ,medicine.anatomical_structure ,Anesthesia ,Neuropathic pain ,biology.protein ,Neuralgia ,medicine.symptom ,business ,Neuroscience - Abstract
Neuropathic pain is a common and often incapacitating clinical problem for which little useful therapy is presently available. Painful peripheral neuropathies can have many etiologies, among which are trauma, viral infections, exposure to radiation or chemotherapy, and metabolic or autoimmune diseases. Sufferers generally experience both pain at rest and exaggerated, painful sensitivity to light touch. Spontaneous firing of injured nerves is believed to play a critical role in the induction and maintenance of neuropathic pain syndromes. Using a well characterized nerve ligation model in the rat, we demonstrate that hyperpolarization-activated, cyclic nucleotide-modulated (HCN) "pacemaker" channels play a previously unrecognized role in both touch-related pain and spontaneous neuronal discharge originating in the damaged dorsal root ganglion. HCN channels, particularly HCN1, are abundantly expressed in rat primary afferent somata. Nerve injury markedly increases pacemaker currents in large-diameter dorsal root ganglion neurons and results in pacemaker-driven spontaneous action potentials in the ligated nerve. Pharmacological blockade of HCN activity using the specific inhibitor ZD7288 reverses abnormal hypersensitivity to light touch and decreases the firing frequency of ectopic discharges originating in Abeta and Adelta fibers by 90 and 40%, respectively, without conduction blockade. These findings suggest novel insights into the molecular basis of pain and the possibility of new, specific, effective pharmacological therapies.
- Published
- 2003
25. Peripheral Neuronal Mechanism of Itch: Histamine and Itch
- Author
-
Kayvan Kazerouni, Sandra R. Chaplan, Itch Robin L. Thurmond, Andrew Greenspan, and Histamine
- Subjects
chemistry.chemical_compound ,Allergy ,chemistry ,business.industry ,Immunology ,Medical profession ,Medicine ,Gastric acid ,business ,medicine.disease ,Local edema ,Histamine ,Anaphylaxis - Abstract
The study of the physiological effects of histamine has a long history, spanning more than a century. Drugs that target histamine have been very successful, and even those not in the medical profession recognize that “antihistamines” are effective treatments for the symptoms of allergies and rhinitis. Histamine research has also spawned a wealth of scientific literature, and a search of the term “histamine” in PubMed yields almost 80,000 references. Even back in 1953, Sir Henry Dale himself said in his memoirs that histamine “…is by now almost too familiar” (Dale 1953, p. 119). Yet new functions are still being uncovered, and this is prompting the development of new drugs that target histamine.Histamine results from the decarboxylation of histidine, and was first described synthetically by Windaus and Vogt in 1907 (Windaus and Vogt 1907). Shortly thereafter, Dale and colleagues found that it was a natural constituent of ergot, which was potent in inducing contraction of certain muscles (Barger and Dale 1910; Dale and Laidlaw 1911). Further work suggested that the effects of histamine were similar to those seen with anaphylaxis (Dale and Laidlaw 1911). Interestingly, Dale did not use the obvious name, histamine, as he explained in his memoirs (Dale 1953), because it was claimed to be too similar to a trademark; Dale instead used the chemical name β-iminazolylethylamine. In addition to this, Dale took great care in his early work not to suggest that histamine was actually involved in normal physiological processes: “…a possibility that was almost clamouring to be recognized,” in his own words (Dale 1953, p. 337). The statement that histamine played a physiological role in vivo had to await the proof of its existence as a natural component of tissue. This was hinted at by early work (Barger and Dale 1911; Abel and Kubota 1919) but was not shown conclusively until 1927 (Best et al. 1927). By 1929, in his Croonain Lectures, Dale readily acknowledged that histamine was a normal constituent of many tissues (Dale 1929).We now know that histamine is produced by many cell types and can be stored by cells such as mast cells, basophils, enterochromaffin-like cells, and neurons. Release from these cells mediates many of the functions that we now intimately associate with histamine, i.e., allergy, gastric acid secretion, neuron transmission, anaphylaxis, etc. Early work linked histamine with responses to trauma in the skin. Injury, firm stroking of the skin, or many other stimuli cause a triple response of local vasodilation, local edema, and flare, which were described in work by Sir Thomas Lewis and coworkers and summarized in his book, The Blood Vessels of the Human Skin (Lewis 1927). Lewis recognized that injury to the skin liberated a substance that resembled, at least in its action, histamine. He carefully termed this the H-substance because there was no proof that histamine existed in skin, although it was clear he suspected the agent was histamine. He states, “…it is difficult to refrain from stating without reserve the simple conclusion that the vasodilator substance considered and the H-substance are one and the same, and that this substance is histamine” (Lewis 1927, p. 235). Others were not as cautious. In his 1929 Croonain Lectures, Dale discussed this in depth and concluded that “…the suggestion was obvious that…Lewis’ H-substance, was histamine itself, not newly formed…but already existing…”, although he acknowledged that final proof required the substance to be isolated (Dale 1929, p. 1235).
- Published
- 2014
26. Vincristine-induced allodynia in the rat
- Author
-
Natsuko Nozaki-Taguchi, Emiliano S. Higuera, Sandra R. Chaplan, Reginald C Ajakwe, and Tony L. Yaksh
- Subjects
Male ,Pain Threshold ,Vincristine ,Hot Temperature ,Cyclohexanecarboxylic Acids ,Gabapentin ,Analgesic ,Pregabalin ,Pain ,Tetrodotoxin ,Acetates ,Rats, Sprague-Dawley ,medicine ,Animals ,Amines ,gamma-Aminobutyric Acid ,Pain Measurement ,Analgesics ,business.industry ,Body Weight ,Antineoplastic Agents, Phytogenic ,Rats ,Anesthesiology and Pain Medicine ,Allodynia ,Neurology ,Anesthesia ,Hyperalgesia ,Neuropathic pain ,Morphine ,Neurology (clinical) ,medicine.symptom ,business ,Excitatory Amino Acid Antagonists ,Ion Channel Gating ,medicine.drug - Abstract
The aims of this study were two-fold: first, to simplify the method for creating a recently described neuropathic pain model in the rat, and second, to evaluate the effects of a number of drugs with analgesic or antihyperalgesic properties, in this model. Continuous intravenous vincristine infusion (1-100 microg kg(-1) day (-1)) for 14 days resulted in a dose dependent tactile allodynia (as measured by von Frey filaments) by 7 days at doses between 30 - 100 microg kg(-1) day (-1), with a hindlimb motor deficit observed at doses greater than 50 microg kg(-1) day (-1). No thermal hyperalgesia was observed. Systemic morphine, lidocaine, mexiletine and pregabalin (given intraperitoneally) produced significant reduction of the allodynia, while tetrodotoxin was without effect. Continuous intravenous infusion of vincristine in rats thus provides a reliable model of chemotherapy induced neuropathy which may be used in defining the mechanism and pharmacology of this clinically relevant condition.
- Published
- 2001
27. Upregulation of Dorsal Root Ganglion α2δ Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats
- Author
-
Z. David Luo, Mark E. Williams, Tony L. Yaksh, Kenneth A. Stauderman, Sandra R. Chaplan, Linda S. Sorkin, and Emiliano S. Higuera
- Subjects
Male ,medicine.medical_specialty ,Nerve Crush ,Rhizotomy ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Ganglia, Spinal ,Internal medicine ,Animals ,Medicine ,Neurons, Afferent ,RNA, Messenger ,ARTICLE ,Ligation ,Pain Measurement ,Behavior, Animal ,business.industry ,General Neuroscience ,Nerve injury ,Sciatic Nerve ,Axons ,Rats ,Up-Regulation ,Disease Models, Animal ,Protein Subunits ,Spinal Nerves ,Allodynia ,Endocrinology ,medicine.anatomical_structure ,Hyperalgesia ,Spinal nerve ,Neuropathic pain ,Peripheral nerve injury ,Neuralgia ,Calcium Channels ,Sciatic nerve ,medicine.symptom ,business ,Neuroscience - Abstract
Peripheral nerve injury can lead to a persistent neuropathic pain state in which innocuous tactile stimulation elicits pain behavior (tactile allodynia). Spinal administration of the anticonvulsant gabapentin suppresses allodynia by an unknown mechanism. In vitro studies indicate that gabapentin binds to the alpha(2)delta-1 (hereafter referred to as alpha(2)delta) subunit of voltage-gated calcium channels. We hypothesized that nerve injury may result in altered alpha(2)delta subunit expression in spinal cord and dorsal root ganglia (DRGs) and that this change may play a role in neuropathic pain processing. Using a rat neuropathic pain model in which gabapentin-sensitive tactile allodynia develops after tight ligation of the left fifth and sixth lumbar spinal nerves, we found a17-fold, time-dependent increase in alpha(2)delta subunit expression in DRGs ipsilateral to the nerve injury. Marked alpha(2)delta subunit upregulation was also evident in rats with unilateral sciatic nerve crush, but not dorsal rhizotomy, indicating a peripheral origin of the expression regulation. The increased alpha(2)delta subunit expression preceded the allodynia onset and diminished in rats recovering from tactile allodynia. RNase protection experiments indicated that the DRG alpha(2)delta regulation was at the mRNA level. In contrast, calcium channel alpha(1B) and beta(3) subunit expression was not co-upregulated with the alpha(2)delta subunit after nerve injury. These data suggest that DRG alpha(2)delta regulation may play an unique role in neuroplasticity after peripheral nerve injury that may contribute to allodynia development.
- Published
- 2001
28. Neuronal Nitric Oxide Synthase mRNA Upregulation in Rat Sensory Neurons after Spinal Nerve Ligation: Lack of a Role in Allodynia Development
- Author
-
Z. David Luo, Brian Scott, Tony L. Yaksh, Sandra R. Chaplan, Nigel A. Calcutt, and Dasa Cizkova
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Diabetic neuropathy ,Transcription, Genetic ,Pain ,Nitric Oxide Synthase Type I ,Gene Expression Regulation, Enzymologic ,Article ,Nitric oxide ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Species Specificity ,Ganglia, Spinal ,Internal medicine ,medicine ,Animals ,Neurons, Afferent ,RNA, Messenger ,business.industry ,General Neuroscience ,Nerve injury ,medicine.disease ,Spinal cord ,Rats ,Spinal Nerves ,medicine.anatomical_structure ,Endocrinology ,Allodynia ,nervous system ,chemistry ,Anesthesia ,Hyperalgesia ,Peripheral nerve injury ,Nitric Oxide Synthase ,medicine.symptom ,Ligation ,business - Abstract
Pharmacological evidence suggests a functional role for spinal nitric oxide (NO) in the modulation of thermal and/or inflammatory hyperalgesia. To assess the role of NO in nerve injury-induced tactile allodynia, we examined neuronal NO synthase (nNOS) expression in the spinal cord and dorsal root ganglia (DRG) of rats with tactile allodynia because of either tight ligation of the left fifth and sixth lumbar spinal nerves or streptozotocin-induced diabetic neuropathy. RNase protection assays indicated that nNOS mRNA (1) was upregulated in DRG, but not spinal cord, neurons on the injury side beginning 1 d after nerve ligation, (2) peaked (∼10-fold increase) at 2 d, and (3) remained elevated for at least 13 weeks. A corresponding increase in DRG nNOS protein was also observed and localized principally to small and occasionally medium-size sensory neurons. In rats with diabetic neuropathy, there was no significant change in DRG nNOS mRNA. However, similar increases in DRG nNOS mRNA were observed in rats that did not develop allodynia after nerve ligation and in rats fully recovered from allodynia 3 months after the nerve ligation. Systemic treatment with a specific pharmacological inhibitor of nNOS failed to prevent or reverse allodynia in nerve-injured rats. Thus, regulation of nNOS may contribute to the development of neuronal plasticity after specific types of peripheral nerve injury. However, upregulation of nNOS is not responsible for the development and/or maintenance of allodynia after nerve injury.
- Published
- 1999
29. Mechanisms and Mediators of Neuropathic Pain
- Author
-
Annika B. Malmberg, Sandra R. Chaplan, Annika B. Malmberg, and Sandra R. Chaplan
- Subjects
- Immunology, Neurosciences, Pain medicine, Life sciences
- Abstract
Numerous improvements in our understanding of the mechanisms that underlie neuropathic pain states have come from the development of animal models, most of which involve partial peripheral nerve injury. The animal models have shown that nerve injury initiates a cascade of events resulting in altered neurochemistry and molecular biology of the peripheral neurons, the dorsal root ganglion cell, and changes in neurotransmitter and receptor expression in the dorsal horn of the spinal cord. Moreover, nerve injury produces anatomical changes with functional consequences. This volume summarises the current understanding of the pathophysiological processes in the peripheral and central nervous system that contribute to the neuropathic pain. It provides a timely review of neuropathic pain mechanisms, written by experts in the field.
- Published
- 2012
30. Spinal pharmacology of tactile allodynia in diabetic rats
- Author
-
Nigel A. Calcutt and Sandra R. Chaplan
- Subjects
Pharmacology ,Agonist ,business.industry ,medicine.drug_class ,Calcium channel ,Central nervous system ,Antagonist ,Receptor antagonist ,chemistry.chemical_compound ,medicine.anatomical_structure ,Allodynia ,chemistry ,Medicine ,NMDA receptor ,NBQX ,medicine.symptom ,business - Abstract
1. Rats develop tactile allodynia to stimulation of the plantar surface of the hindpaw with von Frey filaments within days of the onset of streptozotocin-induced diabetes. This is prevented by insulin and alleviated by systemic lignocaine, but the aetiology is unknown. 2. Using indwelling lumbar intrathecal catheters to deliver pharmacological agents, we have investigated whether tactile allodynia in streptozotocin-diabetic rats is dependent on mechanisms associated with spinal sensitization, by assessing the efficacy of agents that inhibit specific components of spinal nociceptive processing. 3. Dose-dependent inhibition of tactile allodynia in diabetic rats was noted with the N-type calcium channel antagonist SNX 239, the alpha2-adrenoceptor agonist dexmedetomidine, the mu-opioid receptor agonist morphine, the N-methyl-D-aspartate (NMDA) receptor antagonist AP5 and the non-NMDA receptor antagonist NBQX. 4. No effect on tactile allodynia was noted after intrathecal administration of the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME), the cyclo-oxygenase inhibitor ketorolac, the L-type calcium channel inhibitor diltiazem or any vehicle. 5. These data suggest that the tactile allodynia of diabetic rats involves spinal glutamatergic pathways but is not associated with spinal release of nitric oxide or prostaglandins.
- Published
- 1997
31. PHYSIOLOGY AND PHARMACOLOGY OF NEUROPATHIC PAIN
- Author
-
Sandra R. Chaplan and Tony L. Yaksh
- Subjects
Anesthesiology and Pain Medicine ,integumentary system ,business.industry ,Anesthesia ,Neuropathic pain ,Medicine ,business ,Foot (unit) ,Burning Sensation - Abstract
In our early experience of nerve wounds, we met with … men suffering from a pain … described as "mustard red-hot" or as a "red-hot file rasping the skin." Its favored site is the foot or hand. The part itself is not alone subject to an intense burning sensation, but becomes exquisitely hyperesthetic, so that a touch or tap of the finger increases the pain. Exposure to the air is avoided by the patient with a care that seems absurd. WEIR-MITCHELL, ET AL, Gunshot Wounds and Other Injuries of Nerves, 1864 80
- Published
- 1997
32. An Improved Method for the Measurement of Lidocaine and Its Metabolites in Rat Plasma
- Author
-
Tony L. Yaksh, Lee R. Hagey, Steven S. Rossi, Sandra R. Chaplan, and Alan C. Moore
- Subjects
Male ,Pharmacology ,Detection limit ,Chromatography ,Lidocaine ,Chemistry ,Rats ,Bioavailability ,Rats, Sprague-Dawley ,Pharmacokinetics ,medicine ,Animals ,Pharmacology (medical) ,Chromatography, Thin Layer ,Solid phase extraction ,Gas chromatography ,Glucuronide ,Quantitative analysis (chemistry) ,medicine.drug - Abstract
An improved method is described for the quantitation of lidocaine and its dominant metabolites in rat plasma, 3-hydroxy-lidocaine glucuronide and 3-hydroxy-MEG-X glucuronide. Frozen plasma samples (100-200 microliters) were thawed and deproteinated by precipitation with acetonitrile, before the conversion of glucuronidates into their respective hydroxylated forms by acid hydrolysis. After extraction with solid-phase C18 cartridge chromatography, the metabolites and parent drug were analyzed by capillary gas chromatography-nitrogen phosphorus detection, without derivativization. A detection limit of 0.005 microgram/ml for lidocaine and nonglucuronidated metabolites and 0.01 microgram/ml for glucuronidated metabolites was achieved. The method offers significant improvements in sensitivity relative to existing techniques, which should be of specific benefit to studies in which sample volume is limited, such as those concerned with the pharmacokinetics of lidocaine metabolism in small-animal pain state models.
- Published
- 1997
33. Agonizing over pain terminology
- Author
-
Linda S. Sorkin and Sandra R. Chaplan
- Subjects
medicine.medical_specialty ,Psychotherapist ,business.industry ,General Neuroscience ,Alternative medicine ,medicine.disease ,humanities ,Terminology ,Surgery ,Dilemma ,stomatognathic diseases ,Anesthesiology and Pain Medicine ,Complex regional pain syndrome ,medicine ,Neurology (clinical) ,business - Abstract
Pain terminology as used by basic and clinical scientists as well as clinicians is frequently inconsistent. Too often people use the same word to mean mechanistically different things or avoid the dilemma by coining their own terms. It is the purpose of this article to point out some of these instances and to encourage open-minded reevaluation of current pain terminology.
- Published
- 1997
34. Tactile allodynia and formalin hyperalgesia in streptozotocin-diabetic rats: effects of insulin, aldose reductase inhibition and lidocaine
- Author
-
Sandra R. Chaplan, Michael C Jorge, Tony L. Yaksh, and Nigel A. Calcutt
- Subjects
Blood Glucose ,Diabetic neuropathy ,medicine.medical_treatment ,Drug Evaluation, Preclinical ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,Diabetic Neuropathies ,Aldehyde Reductase ,Formaldehyde ,Diabetes mellitus ,Animals ,Insulin ,Medicine ,Anesthetics, Local ,Enzyme Inhibitors ,business.industry ,Lidocaine ,medicine.disease ,Streptozotocin ,Aldose reductase inhibitor ,Rats ,nervous system diseases ,Anesthesiology and Pain Medicine ,Peripheral neuropathy ,Allodynia ,Neurology ,Hyperalgesia ,Touch ,Sensory Thresholds ,Anesthesia ,Female ,Neurology (clinical) ,medicine.symptom ,business ,medicine.drug - Abstract
Rats developed tactile allodynia within days of the onset of diabetes and which persisted for up to 8 weeks. Allodynia was prevented by insulin therapy that maintained normoglycemia while established allodynia was reversed by insulin therapy and normoglycemia of days but not hours duration. Tactile allodynia persisted in diabetic rats that received enough insulin to maintain normal body and foot weights but remained hyperglycemic, whereas this therapy was sufficient to correct other nerve disorders in diabetic rats, including deficits of sensory and motor nerve conduction velocity, nerve blood flow and hyperalgesia during the formalin test. Treating diabetic rats with the aldose reductase inhibitor ICI 222155 did not prevent tactile allodynia. Tactile allodynia was of similar magnitude in diabetic rats and nerve injured control rats and diabetes did not alter the magnitude or time course of nerve injury-induced allodynia. Systemic lidocaine treatment alleviated tactile allodynia in nerve injured control rats and both sham-operated and nerve injured diabetic rats. The streptozotocin-diabetic rat develops tactile allodynia that appears to be related to prolonged periods of insulin deficiency or hyperglycemia and which is amenable to treatment with lidocaine. The model may be of use in investigating the efficacy of other potential therapeutic agents for treating painful diabetic neuropathy.
- Published
- 1996
35. Rethinking reflex sympathetic dystrophy
- Author
-
Sandra R. Chaplan
- Subjects
medicine.medical_specialty ,Anesthesiology and Pain Medicine ,business.industry ,General Neuroscience ,Internal medicine ,Cardiology ,medicine ,Reflex ,Dystrophy ,Neurology (clinical) ,business - Published
- 1996
36. Prolonged Alleviation of Tactile Allodynia by Intravenous Lidocaine in Neuropathic Rats
- Author
-
Flemming W. Bach, Steven L. Shafer, Tony L. Yaksh, and Sandra R. Chaplan
- Subjects
Male ,Lidocaine ,medicine.drug_class ,Pain ,Tactile Allodynia ,Rats, Sprague-Dawley ,Route of administration ,medicine ,Animals ,Anesthetics, Local ,Neurons ,Dose-Response Relationship, Drug ,Local anesthetic ,business.industry ,Peripheral Nervous System Diseases ,Nerve injury ,Rats ,Anesthesiology and Pain Medicine ,Allodynia ,Mechanism of action ,Anesthesia ,Injections, Intravenous ,Neuropathic pain ,medicine.symptom ,business ,medicine.drug - Abstract
Background Lidocaine may be useful in the treatment of neuropathic pain states. The authors hypothesized that lidocaine would reduce tactile allodynia observed in a rat nerve injury model. In an effort to determine the site of drug action, effects after intravenous, intrathecal, and regional administration were compared. Methods Rats underwent ligation of the left fifth and sixth lumbar spinal nerves. The 50% thresholds (g) for left hind paw withdrawal of awake rats to von Frey hairs were documented before, during, and after intravenous administration of lidocaine at programmed/documented pseudo-steady-state plasma concentrations, and correlated with measured plasma concentrations. Responses to lidocaine application intrathecally and regionally to the injured nerves were also recorded. Results In rats with tactile allodynia, intravenous lidocaine yielded 66 +/- 11% of the maximal possible effect on thresholds (100% = normal threshold), versus -1.3 +/- 2.7% for saline infusion. Twenty-one days after lidocaine infusion, 30-40% of the maximal possible effect persisted. Threshold increases depended on plasma concentration, rather than quantity of drug administered: rats receiving 15 mg/kg with higher plasma concentrations (1.2 +/- 0.1 micrograms/ml) showed significant allodynia suppression throughout 7 days of follow-up, whereas rats receiving 15 mg/kg at a slower rate with lower plasma concentrations (0.6 +/- 0.1 microgram/ml) did not. The EC50 for acute allodynia suppression was 0.75 microgram/ml. No such allodynia suppression was seen after intrathecal or regional administration of lidocaine despite transient neural blockade. Conclusions Intravenous, but not intrathecal or regionally applied, lidocaine produces dose-dependent suppression of allodynia associated with nerve injury. The effects far outlast plasma concentrations of lidocaine. The mechanism of these prolonged effects is unknown.
- Published
- 1995
37. Systemic and supraspinal, but not spinal, opiates suppress allodynia in a rat neuropathic pain model
- Author
-
Youn-Woo Lee, Tony L. Yaksh, and Sandra R. Chaplan
- Subjects
Agonist ,Pyrrolidines ,medicine.drug_class ,Narcotic Antagonists ,Methysergide ,Pain ,(+)-Naloxone ,Motor Activity ,Pharmacology ,Catalepsy ,Rats, Sprague-Dawley ,Peripheral Nerve Injuries ,medicine ,Animals ,Injections, Spinal ,Injections, Intraventricular ,Analgesics ,Morphine ,Naloxone ,business.industry ,General Neuroscience ,digestive, oral, and skin physiology ,3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer ,Enkephalins ,medicine.disease ,Rats ,Analgesics, Opioid ,Allodynia ,nervous system ,Opioid ,Anesthesia ,Neuropathic pain ,medicine.symptom ,Enkephalin, D-Penicillamine (2,5) ,business ,Injections, Intraperitoneal ,psychological phenomena and processes ,hormones, hormone substitutes, and hormone antagonists ,medicine.drug - Abstract
The effects of intraperitoneal (I.P.), intracerebroventricular (ICV) and intrathecal (IT) opiates were studied in the rat neuropathic pain model of Kim and Chung. Dose dependent reduction of allodynia was observed after I.P. and ICV morphine, but not after IT morphine, IT or ICV c[D-pen2 D-pen5]enkephalin (DPDPE) (delta agonist), or IT or ICV U50488H (kappa agonist). The effects of ICV morphine were blocked by I.P. naloxone, but not by IT methysergide, phentolamine or 8-sulfophenyltheophylline. Catalepsy (immobility) was observed after IT, ICV and IT morphine but this was not reliably associated with a reduction of allodynia. I.P. and ICV morphine may thus reduce tactile allodynia via supraspinal, but not spinal, mu opioid receptors.
- Published
- 1995
38. Heteroaryl urea inhibitors of fatty acid amide hydrolase: structure-mutagenicity relationships for arylamine metabolites
- Author
-
William M. Jones, Mark S. Tichenor, Sean Brown, Natalie A. Hawryluk, James A. Palmer, Lin Luo, Marlies De Boeck, Filip Woestenborghs, J. Guy Breitenbucher, Michelle Wennerholm, Joan Pierce, D. Beerens, Michael Webb, John M. Keith, Sandy J. Wilson, Jeff Merit, Sandra R. Chaplan, Mark Seierstad, and Mark J. Karbarz
- Subjects
Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Amidohydrolases ,Mixed Function Oxygenases ,Serine ,chemistry.chemical_compound ,Structure-Activity Relationship ,Fatty acid amide hydrolase ,Drug Discovery ,Structure–activity relationship ,Organic chemistry ,Animals ,Humans ,Urea ,Amines ,Enzyme Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Mutagenicity Tests ,Organic Chemistry ,Aromatic amine ,Active site ,Rats ,Electrophile ,biology.protein ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Amine gas treating ,Mutagens - Abstract
The structure-activity relationships for a series of heteroaryl urea inhibitors of fatty acid amide hydrolase (FAAH) are described. Members of this class of inhibitors have been shown to inactivate FAAH by covalent modification of an active site serine with subsequent release of an aromatic amine from the urea electrophile. Systematic Ames II testing guided the optimization of urea substituents by defining the structure-mutagenicity relationships for the released aromatic amine metabolites. Potent FAAH inhibitors were identified having heteroaryl amine leaving groups that were non-mutagenic in the Ames II assay.
- Published
- 2012
39. Quantitative assessment of tactile allodynia in the rat paw
- Author
-
J. W. Pogrel, Sandra R. Chaplan, Flemming W. Bach, Tony L. Yaksh, and Jin Mo Chung
- Subjects
Male ,Stimulus (physiology) ,Rats, Sprague-Dawley ,Sensory threshold ,medicine ,Animals ,Nociception assay ,Ligation ,Pain Measurement ,Observer Variation ,Hyperesthesia ,General Neuroscience ,Reproducibility of Results ,medicine.disease ,Rats ,Spinal Nerves ,Peripheral neuropathy ,Allodynia ,Touch ,Sensory Thresholds ,Anesthesia ,Hyperalgesia ,Neuropathic pain ,medicine.symptom ,Psychology - Abstract
We applied and validated a quantitative allodynia assessment technique, using a recently developed rat surgical neuropathy model wherein nocifensive behaviors are evoked by light touch to the paw. Employing von Frey hairs from 0.41 to 15.1 g, we first characterized the percent response at each stimulus intensity. A smooth log-linear relationship was observed, with a median 50% threshold at 1.97 g (95% confidence limits, 1.12-3.57 g). Subsequently, we applied a paradigm using stimulus oscillation around the response threshold, which allowed more rapid, efficient measurements. Median 50% threshold by this up-down method was 2.4 g (1.81-2.76). Correlation coefficient between the two methods was 0.91. In neuropathic rats, good intra- and inter-observer reproducibility was found for the up-down paradigm; some variability was seen in normal rats, attributable to extensive testing. Thresholds in a sizable group of neuropathic rats showed insignificant variability over 20 days. After 50 days, 61% still met strict neuropathy criteria, using survival analysis. Threshold measurement using the up-down paradigm, in combination with the neuropathic pain model, represents a powerful tool for analyzing the effects of manipulations of the neuropathic pain state.
- Published
- 1994
40. Dynamic changes in the TRPA1 selectivity filter lead to progressive but reversible pore dilation
- Author
-
Tue G. Banke, Alan D. Wickenden, and Sandra R. Chaplan
- Subjects
Agonist ,Purinergic P2 Receptor Agonists ,Cell Membrane Permeability ,Physiology ,medicine.drug_class ,TRPM Cation Channels ,TRPV Cation Channels ,Nerve Tissue Proteins ,CHO Cells ,Transfection ,Transient receptor potential channel ,Cricetulus ,Dogs ,Meglumine ,Transient Receptor Potential Channels ,Isothiocyanates ,Cricetinae ,Membrane Transport Modulators ,medicine ,Animals ,Humans ,TRPA1 Cation Channel ,Benzoxazoles ,Voltage-dependent calcium channel ,Dose-Response Relationship, Drug ,Chemistry ,Receptors, Purinergic P2 ,Quinolinium Compounds ,Cell Membrane ,Gap junction ,Cell Biology ,Pannexin ,Farnesol ,Sensory neuron ,Salicylates ,Rats ,Kinetics ,medicine.anatomical_structure ,Biochemistry ,Benzamides ,Biophysics ,Calcium ,Calcium Channels ,Carbamates ,Receptors, Purinergic P2X7 ,Ion Channel Gating - Abstract
TRPA1 is a nonselective cation channel belonging to the transient receptor potential (TRP) family that is expressed in peripheral sensory neurons and may play important roles in pain perception and inflammation. We found that agonist stimulation of TRPA1, along with other members of the TRP family (TRPV1–4 and TRPM8), can induce the appearance of a large pore permeable to large organic cations such as Yo-Pro (YP) and N-methyl-d-glucamine, in an agonist and divalent cation-dependent manner. YP uptake was not inhibited by a panel of putative gap junction/pannexin blockers, suggesting that gap junction proteins are not required in this process. Our data suggest that changes in the TRP channel selectivity filter itself result in a progressive but reversible pore dilation process, a process that is under strong regulation by external calcium ions. Our data suggest that calcium plays a novel role in setting the amount of time TRPA1 channels spend in a dilated state providing a mechanism that may limit sensory neuron activation by painful or irritating substances.
- Published
- 2010
41. PHARMACOLOGICAL CHARACTERIZATION OF A PURINERGIC RECEPTOR (P2X7) ANTAGONIST IN‐VITRO AND IN‐VIVO
- Author
-
Traci Olafson, Nyantsz Wu, Robert Neff, Alan D. Wickenden, Alec D. Lebsack, Jamie M Freedman, Qi Wang, Anindya Bhattacharya, Hong Ao, Michael P. Maher, Sandra R. Chaplan, Natalie A. Hawryluk, William A Eckert, and William M. Jones
- Subjects
Chemistry ,In vivo ,Purinergic receptor ,Genetics ,Antagonist ,Enzyme-linked receptor ,Pharmacology ,Molecular Biology ,Biochemistry ,In vitro ,Biotechnology - Published
- 2010
42. Neuropathic Pain
- Author
-
Sandra R. Chaplan
- Subjects
Voltage-dependent calcium channel ,business.industry ,MEDLINE ,Pain ,General Medicine ,Calcium Channel Blockers ,omega-Conotoxins ,Rats ,Electrophysiology ,Calcium Channels, N-Type ,Text mining ,Anesthesiology and Pain Medicine ,Neuropathic pain ,Animals ,Humans ,Medicine ,Nervous System Diseases ,business ,Neuroscience - Published
- 2000
43. HCN pacemaker channels and pain: a drug discovery perspective
- Author
-
Alan D. Wickenden, Michael P. Maher, and Sandra R. Chaplan
- Subjects
Potassium Channels ,Sensory Receptor Cells ,medicine.medical_treatment ,Cyclic Nucleotide-Gated Cation Channels ,Pain ,Models, Biological ,Cardiac pacemaker ,chemistry.chemical_compound ,Drug Discovery ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,Medicine ,Animals ,Humans ,Cyclic adenosine monophosphate ,Pharmacology ,Analgesics ,Molecular Structure ,business.industry ,Hyperpolarization (biology) ,Nerve injury ,Electrophysiology ,Allodynia ,chemistry ,Anesthesia ,Mechanosensitive channels ,medicine.symptom ,business ,Ivabradine ,Neuroscience ,medicine.drug - Abstract
This article reviews evidence that hyperpolarization-activated, cation nonselective (HCN) channels, the molecular basis of the Ih current, potentially represent valid targets for novel analgesic agents. Ih is a prominent current in many peripheral sensory nerves, with highest current density typically found in large diameter neurons. Recent data suggest that Ih may represent a valid target for the treatment of spontaneous pain and allodynia associated with nerve injury. The majority of available electrophysiological and molecular evidence suggests that fast activating, weakly cyclic adenosine monophosphate (cAMP) sensitive HCN1-based channels may make a significant contribution to Ih, especially in large diameter, mechanosensitive fibers, where the Ih current appears to support abnormal spontaneous firing after nerve injury. In contrast, HCN4 channels seem to play the predominant role in cardiac pacemaker tissue. These observations raise the possibility that HCN1 selective blockers may inhibit pain associated with nerve injury without dramatic effects on heart rate. Development of novel HCN blocking analgesics presents a number of significant technical challenges. Although a number of HCN blockers are available, such as ZD-7288, ivabradine, and others, these drugs inhibit all HCN isoforms with the same potency. As a result, these compounds have powerful effects on heart rate, severely limiting their utility for non-cardiac indications such as pain. Selectivity challenges, mechanisms of compound interaction with the channel, and assay methods are described in detail.
- Published
- 2009
44. In‐vitro and in‐vivo pharmacology of a novel TRPV1 receptor antagonist: JNJ38748021
- Author
-
Michael P. Maher, Sandra R. Chaplan, James Guy Breitenbucher, Qi Wang, Anindya Bhattacharya, Nadia Nasser, Michael D. Hack, Jeffrey E. Merit, Hong Ao, Natalie A. Hawryluk, Mena Kansagara, Brian Scott, Alan D. Wickenden, and Chui-Se Tham
- Subjects
In vivo ,Chemistry ,Genetics ,Antagonist ,Pharmacology ,Molecular Biology ,Biochemistry ,In vitro ,Biotechnology ,TRPV1 receptor - Published
- 2008
45. Fatty acid amide hydrolase inhibition enhances the anti-allodynic actions of endocannabinoids in a model of acute pain adapted for the mouse
- Author
-
J.A. Palmer, Sandra R. Chaplan, Leon Chang, and E.S. Higuera
- Subjects
Male ,Cannabinoid receptor ,Polyunsaturated Alkamides ,medicine.medical_treatment ,Glycine ,Pain ,Arachidonic Acids ,Pharmacology ,Amidohydrolases ,Glycerides ,chemistry.chemical_compound ,Mice ,Mice, Congenic ,Fatty acid amide hydrolase ,Cannabinoid Receptor Modulators ,medicine ,Animals ,Enzyme Inhibitors ,Receptor ,Chemistry ,General Neuroscience ,Chronic pain ,Anandamide ,medicine.disease ,Endocannabinoid system ,Mice, Inbred C57BL ,Disease Models, Animal ,Allodynia ,Biochemistry ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,medicine.symptom ,Burns ,Endocannabinoids - Abstract
Cannabinoid ligands have been shown to be anti-nociceptive in animal models of acute and chronic pain by acting at the two known cannabinoid receptors, cannabinoid-1 receptor (CB-1) and cannabinoid-2 receptor (CB-2). A major concern with the use of cannabinoids for pain relief is that they activate receptors at sites other than those involved in the transmission of nociceptive stimuli. An alternative approach is to target the naturally occurring endocannabinoids, such as anandamide (AEA), 2-arachidonylglycerol (2-AG) and N -arachidonylglycine ( N -AG). However in vivo results obtained with these compounds appear to be weak, most probably due to their rapid degradation and subsequent short half-life. The predominant enzyme responsible for the hydrolysis of anandamide (and some other endocannabinoids) in the brain is fatty acid amide hydrolase (FAAH). Recently, the α-ketoheterocycle OL135 has been synthesized and shown to be a highly potent and selective inhibitor of FAAH with efficacy in pain models in vivo . In the present study, we have adapted the mild thermal injury (MTI) model of acute pain for the mouse and pharmacologically characterized this model by showing significant reversal of the tactile allodynia by morphine (3, 5 and 10 mg kg −1 s.c.), gabapentin (100 and 300 mg kg −1 i.p.), ibuprofen (100 mg kg −1 i.p.) and OL135 (10, 30 and 100 mg kg −1 i.p.). Furthermore we have demonstrated, using this model, that a subtherapeutic dose of OL135 can enable the endocannabinoids AEA and 2-AG, but not N -AG to be active at doses where they are otherwise nonanalgesic (20 mg kg −1 i.p.). The implications of this model in the study of pain in mice, and the therapeutic potential of FAAH inhibition to provide analgesia without the undesirable side effects of direct agonism of cannabinoid receptors are discussed.
- Published
- 2007
46. Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat
- Author
-
Adrienne E. Dubin, Hong Ao, Doo Hyun Lee, Sean Brown, Leon Chang, E.S. Higuera, Sandra R. Chaplan, and Lin Luo
- Subjects
Male ,medicine.medical_specialty ,Potassium Channels ,Sensory Receptor Cells ,Cyclic Nucleotide-Gated Cation Channels ,Pain ,Merkel Cells ,Rats, Sprague-Dawley ,Dorsal root ganglion ,Internal medicine ,Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ,Medicine ,Animals ,Peripheral Nerves ,Skin ,business.industry ,General Neuroscience ,Chronic pain ,Nociceptors ,Cardiovascular Agents ,medicine.disease ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Peripheral neuropathy ,Endocrinology ,Allodynia ,Pyrimidines ,Hyperalgesia ,Peripheral nervous system ,Neuropathic pain ,Peripheral nerve injury ,Acute Disease ,Chronic Disease ,medicine.symptom ,business ,Neuroscience ,Mechanoreceptors - Abstract
Hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels contribute to rhythmic spontaneous activity in the heart and CNS. Ectopic spontaneous neuronal activity has been implicated in the development and maintenance of acute and chronic hyperalgesia, allodynia and spontaneous pain. Previously, we documented that systemic administration of ZD7288, a specific blocker of pacemaker current (I(h)), decreased ectopic activity in dorsal root ganglion (DRG) and reversed tactile allodynia in spinal nerve ligated (SNL) rats [Chaplan SR, Guo HQ, Lee DH, Luo L, Liu C, Kuei C, Velumian AA, Butler MP, Brown SM, Dubin AE (2003) Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J Neurosci 23:1169-1178]. Spontaneous pain is the chief clinical manifestation of peripheral nerve injury; however, a role for I(h) in spontaneous pain has not been described. Here, in further rat studies, we report that systemic administration of ZD7288 reversed spontaneous pain induced by mild thermal injury (MTI) and tactile allodynia induced by SNL and MTI. In contrast, ZD7288 did not reduce thermal hyperalgesia. An important locus of action appears to be in the skin since intraplantar (local) administration of ZD7288 completely suppressed tactile allodynia arising from MTI and SNL and reduced spontaneous pain due to MTI. Immunohistochemical staining of plantar skin sections detected HCN1-HCN4 expression in mechanosensory structures (e.g., Meissner's corpuscles and Merkel cells). Collectively, these data suggest that expression and modulation of I(h) in the peripheral nervous system, including specialized sensory structures, may play a significant role in sensory processing and contribute to spontaneous pain and tactile allodynia.
- Published
- 2006
47. Inhibition of fatty acid amide hydrolase produces analgesia by multiple mechanisms
- Author
-
Leon, Chang, Lin, Luo, James A, Palmer, Steven, Sutton, Sandy J, Wilson, Ann J, Barbier, James Guy, Breitenbucher, Sandra R, Chaplan, and Michael, Webb
- Subjects
Male ,Mice, Knockout ,Analgesics ,Dose-Response Relationship, Drug ,Naloxone ,Polyunsaturated Alkamides ,Pyridines ,Narcotic Antagonists ,Brain ,Pain ,Arachidonic Acids ,Amidohydrolases ,Rats ,Mice, Inbred C57BL ,Rats, Sprague-Dawley ,Mice ,Spinal Cord ,Models, Animal ,Papers ,Animals ,Enzyme Inhibitors ,Endocannabinoids ,Pain Measurement - Abstract
1 The reversible fatty acid amide hydrolase (FAAH) inhibitor OL135 reverses mechanical allodynia in the spinal nerve ligation (SNL) and mild thermal injury (MTI) models in the rat. The purpose of this study was to investigate the role of the cannabinoid and opioid systems in mediating this analgesic effect. 2 Elevated brain concentrations of anandamide (350 pmol g(-1) of tissue vs 60 pmol g(-1) in vehicle-treated controls) were found in brains of rats given OL135 (20 mg kg(-1)) i.p. 15 min prior to 20 mg kg(-1) i.p. anandamide. 3 Predosing rats with OL135 (2-60 mg kg(-1) i.p.) 30 min before administration of an irreversible FAAH inhibitor (URB597: 0.3 mg kg(-1) intracardiac) was found to protect brain FAAH from irreversible inactivation. The level of enzyme protection was correlated with the OL135 concentrations in the same brains. 4 OL135 (100 mg kg(-1) i.p.) reduced by 50% of the maximum possible efficacy (MPE) mechanical allodynia induced by MTI in FAAH(+/+)mice (von Frey filament measurement) 30 min after dosing, but was without effect in FAAH(-/-) mice. 5 OL135 given i.p. resulted in a dose-responsive reversal of mechanical allodynia in both MTI and SNL models in the rat with an ED(50) between 6 and 9 mg kg(-1). The plasma concentration at the ED(50) in both models was 0.7 microM (240 ng ml(-1)). 6 In the rat SNL model, coadministration of the selective CB(2) receptor antagonist SR144528 (5 mg kg(-1) i.p.), with 20 mg kg(-1) OL135 blocked the OL135-induced reversal of mechanical allodynia, but the selective CB(1) antagonist SR141716A (5 mg kg(-1) i.p.) was without effect. 7 In the rat MTI model neither SR141716A or SR144528 (both at 5 mg kg(-1) i.p.), or a combination of both antagonists coadministered with OL135 (20 mg kg(-1)) blocked reversal of mechanical allodynia assessed 30 min after dosing. 8 In both the MTI model and SNL models in rats, naloxone (1 mg kg(-1), i.p. 30 min after OL135) reversed the analgesia (to 15% of control levels in the MTI model, to zero in the SNL) produced by OL135.
- Published
- 2006
48. Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain
- Author
-
Nicholas I. Carruthers, Jeannie Poblete, David Julius, Kazufumi Kubota, Christopher M. Flores, Joseph R. Ghilardi, Theodore H. Lindsay, Adrienne E. Dubin, Heidi Röhrich, Matthew J. Schwei, Devin M. Swanson, Sandra R. Chaplan, Molly A. Sevcik, Kyle G. Halvorson, Patrick W. Mantyh, and Michael A. Kuskowski
- Subjects
Male ,TRPV1 ,Pain ,TRPV Cation Channels ,Bone Neoplasms ,Mice, Transgenic ,Pharmacology ,Bone resorption ,Bone and Bones ,Drug Administration Schedule ,Functional Laterality ,Mice ,Nerve Fibers ,Ganglia, Spinal ,medicine ,Noxious stimulus ,Animals ,Pain Measurement ,Analgesics ,Analysis of Variance ,Activating Transcription Factor 3 ,Behavior, Animal ,Bone cancer ,business.industry ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Chronic pain ,medicine.disease ,Immunohistochemistry ,Sensory neuron ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Nociception ,nervous system ,Anesthesia ,Nociceptor ,Disease Progression ,business ,Brief Communications - Abstract
Cancer colonization of bone leads to the activation of osteoclasts, thereby producing local tissue acidosis and bone resorption. This process may contribute to the generation of both ongoing and movement-evoked pain, resulting from the activation of sensory neurons that detect noxious stimuli (nociceptors). The capsaicin receptor TRPV1 (transient receptor potential vanilloid subtype 1) is a cation channel expressed by nociceptors that detects multiple pain-producing stimuli, including noxious heat and extracellular protons, raising the possibility that it is an important mediator of bone cancer pain via its capacity to detect osteoclast- and tumor-mediated tissue acidosis. Here, we show that TRPV1 is present on sensory neuron fibers that innervate the mouse femur and that, in anin vivomodel of bone cancer pain, acute or chronic administration of a TRPV1 antagonist or disruption of the TRPV1 gene results in a significant attenuation of both ongoing and movement-evoked nocifensive behaviors. Administration of the antagonist had similar efficacy in reducing early, moderate, and severe pain-related responses, suggesting that TRPV1 may be a novel target for pharmacological treatment of chronic pain states associated with bone cancer metastasis.
- Published
- 2005
49. Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist
- Author
-
Nicholas I. Carruthers, Doo Hyun Lee, Scott L. Dax, Curt Mazur, Nadia Nasser, Michele C. Jetter, Lisa Gonzales, Sui-Po Zhang, Michael Bogenstaetter, Swanson Devin M, Adrienne E. Dubin, Brian Lord, Michele C. Rizzolio, Ellen E. Codd, Sandra R. Chaplan, Chandra R. Shah, Leon Chang, J. Guy Breitenbucher, Changlu Liu, and Kenway Hoey
- Subjects
Male ,Pyridinylpiperazine ,Stereochemistry ,medicine.drug_class ,Carboxylic acid ,TRPV1 ,Administration, Oral ,Aminopyridines ,Biological Availability ,TRPV Cation Channels ,Hypothermia ,Chemical synthesis ,Ion Channels ,Piperazines ,Body Temperature ,Cell Line ,chemistry.chemical_compound ,Structure-Activity Relationship ,Amide ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Pain Measurement ,chemistry.chemical_classification ,Analgesics ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Receptor antagonist ,Rats ,Piperazine ,nervous system ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Calcium ,Capsaicin - Abstract
High throughput screening using the recombinant human TRPV1 receptor was used to identify a series of pyridinylpiperazine ureas (3) as TRPV1 vanilloid receptor ligands. Exploration of the structure-activity relationships by parallel synthesis identified the essential pharmacophoric elements for antagonism that permitted further optimization via targeted synthesis to provide a potent orally bioavailable and selective TRPV1 modulator 41 active in several in vivo models.
- Published
- 2005
50. The TRPV1 Vanilloid Receptor: A Target for Therapeutic Intervention
- Author
-
Sandra R. Chaplan, Nicholas I. Carruthers, and J. Guy Breitenbucher
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Intervention (counseling) ,Internal medicine ,TRPV1 ,Medicine ,business ,Receptor - Published
- 2005
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