A5022206066- Pain Mechanisms and Treatments
- Numerical Methods and Algorithms
- Neuroscience and Neuropharmacology Research
- Neuropeptides and Animal Physiology
- Matrix Theory and Algorithms
- Parallel Computing and Optimization Techniques
- Cannabis and Cannabinoid Research
- Advanced Data Storage Technologies
- Digital Filter Design and Implementation
- Inflammatory mediators and NSAID effects
- Ion Channels and Receptors
- Complex Network Analysis Techniques
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Botulinum Toxin and Related Neurological Disorders
- Advanced Numerical Analysis Techniques
- Receptor Mechanisms and Signaling
- Stochastic Gradient Optimization Techniques
- Neurotransmitter Receptor Influence on Behavior
- Herbal Medicine Research Studies
- Beetle Biology and Toxicology Studies
- Cryptography and Data Security
- Pharmacological Effects of Natural Compounds
- Ion channel regulation and function
- Advanced Graph Neural Networks
- Graph theory and applications
Lawrence Livermore National Laboratory
2018-2024
Columbia University Irving Medical Center
2022
Loyola University Maryland
2013
Novartis (Switzerland)
2002-2012
Novartis (United Kingdom)
1999-2007
Novartis Institutes for BioMedical Research
2005
Osteoarthritis (OA) is a major healthcare burden, with increasing incidence. Pain the predominant clinical feature, yet therapy ineffective for many patients. While there are considerable insights into mechanisms underlying tissue remodelling, poor understanding of link between disease pathology and pain. This in part owing to lack animal models that combine both osteoarthritic remodelling Here, we provide an analysis pain related behaviours two OA rat: partial medial meniscectomy...
The efficient utilization of mixed-precision numerical linear algebra algorithms can offer attractive acceleration to scientific computing applications. Especially with the hardware integration low-precision special-function units designed for machine learning applications, traditional community urgently needs reconsider floating point formats used in distinct operations efficiently leverage available compute power. In this work, we provide a comprehensive survey routines, including...
Changes in phenotype or connectivity of primary afferent neurons following peripheral nerve injury may contribute to the hyperalgesia and allodynia associated with neuropathic pain conditions. Although earlier studies using partial models have focused on role damaged fibres generation ectopic discharges pain, it is now thought that remaining undamaged be equally important. We examined expression sensory neuron-specific cation channel Vanilloid Receptor 1 (VR1), an important transducer...
We have examined the effects of cannabinoid agonists on hyperalgesia in a model neuropathic pain rat and investigated possible sites action. The antihyperalgesic activity cannabinoids was compared with their ability to elicit behavioural characteristic central activity. WIN55,212-2 (0.3–10 mg kg−1), CP-55,940 (0.03–1 kg−1) HU-210 (0.001–0.03 were all active 'tetrad' tests consisting tail-flick, catalepsy, rotarod hypothermia following subcutaneous administration, rank order potency each...
Inflammatory processes occurring within the central nervous system (CNS) can produce 'illness induced behaviours' which include fever, sleep and development of allodynia hyperalgesia. Here we demonstrate effects pro-inflammatory mediators, bacterial endotoxin, rat recombinant interleukin 1 beta (rrIL-1 beta) or tumour necrosis factor-alpha (rrTNF alpha) on integration somatosensory information at single neuronal level, via recordings from wide-dynamic range neurones in dorsal horn spinal...
The excitation of nociceptive sensory neurons by ATP released in injured tissue is believed to be mediated partly P2X<sub>3</sub>receptors. Although an analysis P2X<sub>3</sub> knock-out mice has revealed some deficits signaling, detailed the role these receptors hampered lack potent specific pharmacological tools. Here we have used antisense oligonucleotides (ASOs) downregulate examine their models chronic pain rat. ASOs and control missense (180 μg/d) were administered intrathecally naive...
We have examined the effects of a novel GABAB agonist, CGP35024, in models chronic neuropathic (partial sciatic ligation) and inflammatory (Freund's complete adjuvant) pain rat, its inhibitory action on spinal transmission vitro. The CGP35024 were compared with L-baclofen gabapentin. reversed mechanical hyperalgesia following single subcutaneous or intrathecal administration, but did not affect hyperalgesia. Gabapentin only moderately affected administration by either route, produced...
Streptozotocin (STZ)-induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy to assess efficacies potential analgesic agents. We have established this model, and here we question whether changes nocifensive reflex activity, measure hyperalgesia, are genuinely indicative peripheral or may rather be attributed extreme poor health animals. For comparison examined animals with induced by partial ligation sciatic nerve. Diabetic were chronically ill,...
Using a gene expression analysis approach we found that the mRNA encoding lysosomal cysteine protease cathepsin S (CatS) was up-regulated in rat dorsal root ganglia (DRG) following peripheral nerve injury. CatS protein expressed infiltrating macrophages DRG and near site of At both sites progressively increased from day 3 to 14 after In naïve rats, intraplantar injection activated recombinant (rr) (0.3, 1 microg/rat) induced mechanical hyperalgesia developed within half-an-hour, diminished...
1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values 3 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition at concentrations up to 30 (HEK 293 cells transfected human COX-1). 3. whole blood assay, for were 0.13 67 (COX-1/COX-2 selectivity ratio 515). 4. was...
Compression of floating-point data will play an important role in high-performance computing as bandwidth and storage become dominant costs. Lossy compression is powerful, but theoretical results are needed to bound its errors when used store look-up tables, simulation results, or even the solution state during computation. In this paper, we analyze round-off error introduced by ZFP, a lossy algorithm. The stopping criteria for ZFP depends on mode specified user: fixed rate, accuracy,...
Metabotropic glutamate receptor 5 (mGluR5) protein increased after sciatic nerve section in ipsilateral L4 and L5 DRG neuronal profiles, with most of the increase occurring myelinated A-fiber somata. mGluR5 also lamina II spinal cord proximal stump this model. After ligation, immunoreactivity dramatically not only damaged but neighboring undamaged L4. Interestingly, partial section, expression did change either or profiles. Both ligation produced significant mechanical thermal hyperalgesia...
Anti-epileptic drugs (AEDs) are increasingly used for the treatment of neuropathic pain. Oxcarbazepine is a recently introduced AED that effective in treating epilepsy and has an improved side-effect profile compared to existing therapies. Here we have examined effect oxcarbazepine other AEDs model pain rat guinea-pig. carbamazepine (3–100 mg kg−1) did not affect mechanical hyperalgesia or tactile allodynia induced by partial sciatic nerve ligation following oral administration. However,...
CT-3 (ajulemic acid) is a synthetic analogue of metabolite Delta9-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states man. Here we show binds to human cannabinoid receptors vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 56 receptors. In functional GTP-gamma-S assay was an agonist both (EC50 11 13.4 nM, respectively). behavioural models chronic inflammatory the rat, oral administration (0.1-1 mg/kg) produced up 60% reversal mechanical hyperalgesia....
Activation of either B1 or B2 bradykinin receptors by kinins released from damaged tissues contributes to the development and maintenance inflammatory hyperalgesia. Whereas agonists activate sensory neurones directly, were thought only have indirect actions on neurones. The recent discovery constitutive receptor expression in rat nervous system lead us re-investigate role neuronal Therefore we examined regulation dorsal root ganglia a model hyperalgesia, correlated it with hyperalgesic...
The endocannabinoid system is involved in the regulation of gastrointestinal (GI) motility and inflammation. Using peripherally restricted cannabinoid (CB)<sub>1</sub>/CB<sub>2</sub> receptor agonist naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (SAB378), we investigated role peripheral receptors GI development colitis mice. actions SAB378 on whole gut transit, upper colonic propulsion, locomotor activity were C57BL/6N, CB<sub>1</sub> knockout, CB<sub>2</sub> knockout potential for...
Lipopolysaccharide (LPS), an endotoxin, produces pain behavior, inflammation, and changes in immune function. Many of these effects are secondary to the production cytokines. In present study, we investigated effect LPS on releasing function afferent terminals as measured by calcitonin gene-related peptide (CGRP) release ex vivo perfused rat trachea, examined possible role cytokines interleukin-1β (IL-1β) tumor necrosis factor-α (TNF-α) intermediaries this effect. Systemic injection (0.75...
The therapeutic potential of transient receptor vanilloid type 1 (TRPV1) antagonists for chronic pain has been recognized more than a decade. However, preclinical and clinical data revealed that acute pharmacological blockade TRPV1 perturbs thermoregulation, resulting in hyperthermia, which is major hurdle the development these drugs. Here, we describe properties 7-<i>tert</i>-butyl-6-(4-chloro-phenyl)-2-thioxo-2,3-dihydro-1<i>H</i>-pyrido[2,3-<i>d</i>]pyrimidin-4-one (BCTP), antagonist with...
Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that expressed on primary afferent neurons and upregulated following inflammation nerve damage. Blockers of this may have utility in the treatment chronic nociceptive neuropathic pain. Here, we describe optimization from high throughput screening hit, series 6-aryl-7-isopropylquinazolinones are TRPV1 antagonists vitro. We also demonstrate one compound active vivo against capsaicin-induced hyperalgesia models pain rat.
Chronic pain resulting from metastatic bone cancer remains poorly understood and resistant to treatment. Here we have examined the effect of novel COX-2 enzyme inhibitor lumiracoxib in a model rat. Lumiracoxib was administered orally twice daily day 10 20 after injection MRMT-1 tumour cells into one tibia. Mechanical hyperalgesia, measured as reduction weight-bearing ipsilateral limb, development static dynamic allodynia were significantly inhibited by repeated lumaricoxib administration. A...
We describe the properties of a novel nonpeptide kinin B 1 receptor antagonist, NVP‐SAA164, and demonstrate its in vivo activity models inflammatory pain transgenic mice expressing human receptor. NVP‐SAA164 showed high affinity for expressed HEK293 cells ( K i 8 n M ), inhibited increases intracellular calcium induced by desArg 10 kallidin (desArg KD) (IC 50 33 ). While similar was observed monkey fibroblasts 7.7 no rat Cos‐7 cells. In which native deleted gene encoding inserted (hB...