Timothy Ness, MD, PhD - US grants

[unreadable] DESCRIPTION (provided by applicant): Acute and chronic pains originating from the urinary bladder are common clinical entities affecting more than 50% of females at some time in their lives. Some conditions are easy to treat, but others, such as interstitial cystitis, are conditions of visceral hypersensitivity that have proven resistant to diagnosis and treatment. There are multiple proposed etiologies for visceral hypersensitivity conditions including mast cell functional abnormalities, immunologic abnormalities, urothelial abnormalities and primary neuropathic mechanisms but the common theme among them is an eventual sensitization/activation of sensory elements. Abnormalities in the periphery leads to central neurophysiological changes that become expressed as enhanced sensory (pain-urgency) and reflex responses (i.e. reduced bladder capacity) which may outlast "triggering" events within the bladder. This proposal defines the consequences of altered primary afferent function by examining the spinal sites of sensory processing which magnify and prolong the effects of peripheral processes. The hypothesis central to these studies is the following: [unreadable] [unreadable] Pathological urinary bladder pain occurs secondary to a spinal sensitization process produced by repeated or continuous primary afferent activation which leads to a hypersensitivity state in which previously innocuous stimuli produce pain. [unreadable] [unreadable] To delineate mechanisms of this sensitization process, testable hypotheses are proposed: first, that sensitization occurs secondary to the selective activation of one of two spinal dorsal horn neuronal populations; second, that a driving force of this sensitization process is the activation of peripheral K-opioid receptor expressing primary afferents; and finally, it is proposed that spinal neurons which are selectively activated by visceral pain-producing manipulations have axonal projections located in the mid-dorsal spinal cord. To test the critical aspects of these hypotheses, neuronal and physiological responses to urinary bladder distension will be studied. Information gathered as part of these studies will allow for an improved definition of urinary bladder-related spinal nociceptive processing mechanisms and will suggest novel therapeutic interventions for urinary bladder pain which include the use of peripherally acting analgesics and modulation/interruption of selective pain pathways. To allow for methodological expansion, characterization of responses to urinary bladder distension in mice will also be examined.

chronic pain; interstitial cystitis; human therapy evaluation; analgesia; nervous system disorder chemotherapy; pentazocine; morphine; sex hormones; patient oriented research; human subject; clinical research;

age difference; psychomotor tracking; psychomotor reaction time; drug adverse effect; cognition; computer simulation; driving while intoxicated; opiate alkaloid; patient oriented research; clinical research; young adult human (21-34); human old age (65+); psychological tests; human subject;

[unreadable] DESCRIPTION (provided by applicant): Acute and chronic pains originating from the urinary bladder are common clinical entities affecting more than 50% of females at some time in their lives. Some conditions are easy to treat, but others, such as interstitial cystitis (1C), are conditions of bladder hypersensitivity that have proven resistant to diagnosis and treatment. As demonstrated in recently published studies, the PI has examined subjects with 1C using quantitative sensory testing and found them to be hypersensitive to bladder distension and other deep tissue stimuli such as muscle pressure and ischemia. The PI of these human studies has sought to understand this urinary bladder hypersensitivity in a translational manner and so in rodents has defined basic neurophysiological elements of bladder sensation at spinal and supraspinal levels. Using UBD-evoked reflexes as experimental endpoints, clinically-relevant models of bladder hypersensitivity were developed. Unfortunately, it is not known which models of bladder hypersensitivity have the greatest relevance to 1C. A critical next step in the development of model systems for translational research is to systematically test these rodent models of bladder hypersensitivity for similarity or dissimilarity to the selected disease process, 1C. In this competitive renewal the PI seeks to take this next step in translational research by concommitantly examining the effects of a non-pharmacologic, sensation-modifying manipulation known to alter the sensation of pain. Specifically, the proposal examines the effect of Heterotopic Noxious Conditioning Stimulus (HNCS) administration on sensations of humans with 1C and on reflex and neuronal responses in three mechanistically-different, rodent bladder hypersensitivity modelSi using these Aims: Specific Aim #1: To quantitatively compare the presence and magnitude of HNCS effects in human subjects with interstitial cystitis (1C) with matched controls. Specific Aim #2: To quantitatively contrast and compare the magnitude of HNCS effects in rat and murine models of bladder hypersensitivity with appropriate controls. The proposed studies examining HNCS-related effects in the 1C population and in rodent model systems by the same researcher will give insight into the comparability of models of bladder hypersensitivity with pathological processes and thereby increase the translation of basic science to therapeutics for pain. [unreadable] [unreadable] [unreadable]

Affect; Allergy; Analysis, Data; Anxiety; Basal Ganglia; Basal Nuclei; Bladder; Blood flow; Body Tissues; Causality; Central Lobe; Central Nervous System; Cerebellum; Chronic; Clinical; Clinical Trials; Clinical Trials Design; Clinical Trials, Unspecified; Colitis, Mucous; Colon, Irritable; Comorbidity; Condition; Cutaneous; Data; Data Analyses; Deep; Depression; Depth; Diagnosis; Diffuse Myofascial Pain Syndrome; Disease; Disorder; Dysfunction; Esthesia; Etiology; Evaluation; Exhibits; Female; Fibromyalgia; Fibromyositis-Fibromyalgia Syndrome; Fibrositis; Figs; Figs - dietary; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Grant; Heating; Hydrogen Oxide; Hypersensitivity; Ice; Image; Immersion; Immersion Investigative Technique; Insula; Insula of Reil; Interstitial Cystitis; Interview; Invasive; Investigators; Irritable Bowel Syndrome; Ischemia; Island of Reil; Life; MPD syndrome; MRI, Functional; Magnetic Resonance Imaging, Functional; Measures; Medial; Membrum superius; Mental Depression; Metabolic; Methods; Morbidity; Morbidity - disease rate; Muscle; Muscle Tissue; NIDDK; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Digestive Diseases and Kidney Disorders; Nervous System, CNS; Neuraxis; Neurologic; Neurological; Neuropsychologic Tests; Neuropsychological Tests; Numbers; Pain; Painful; Parietal; Patient Selection; Patients; Phenotype; Physiopathology; Population; Pressure; Pressure- physical agent; Process; Purpose; Questionnaires; Recruitment Activity; Reporting; Research Design; Research Personnel; Researchers; Resistance; Rheumatism, Muscular; SUBGP; Sampling; Sampling Studies; Science of neurophysiology; Screening procedure; Sensation; Sensory; Sensory Process; Site; Spin Labels; Staging; Standards; Standards of Weights and Measures; Stimulus; Stratification; Stress; Structure; Study Subject; Study Type; Subgroup; Suggestion; Symptoms; Syndrome; Testing; Thalamic structure; Thalamus; Thinking; Thinking, function; Time; TimeLine; Tissues; Upper Extremity; Upper Limb; Urinary System, Bladder; Visceral; Water; base; clinical investigation; clinical relevance; clinically relevant; cohort; disease causation; disease etiology; disease/disorder; disease/disorder etiology; disorder etiology; experience; fMRI; fibromyalgia syndrome; imaging; innovative technologies; interest; myofascial pain dysfunction syndrome; neurophysiology; neuropsychological; painful bladder syndrome; pathophysiology; pressure; recruit; resistant; response; screening; screenings; sex; spastic colon; study design; thalamic; urinary bladder; urologic; urological

DESCRIPTION (provided by applicant): Chlorine (Cl2) is a highly irritant and reactive gas produced in large quantities throughout the world. Exposure to Cl2 released into the atmosphere during transportation and industrial accidents, as well as acts of terrorism, has resulted in significant lung injury leading to death from respiratory failure or significant morbidty. Our recent data show that there may be benefit to treating subjects exposed to Cl2 with inhaled local anesthetics. The present studies will examine the effects of this treatment as monotherapy or in combination with a beta adrenergic agonist on measures of pain and inflammation in murine models.