1985 — 1987 |
Quock, Raymond Mark |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Nitrous Oxide and Endorphins
Nitrous oxide is widely used clinically for conscious sedation and also in surgical anesthesia, however, the mechanism of its analgesic action has remained unknow. Other investigators have reported that nitrous oxide-induced analgesia is antagonized by the opiate receptor blocker naloxone and, in preliminary investigations, we have found that exposure to 75% nitrous oxide: 25% oxygen produces a reversible increase in the methionine-enkephalin (ME)-like immunoreactivity in fractions of artificial cerebrospinal fluid collected from ventricular-cisternally-perfused, anesthetized rats. Based upon these findings, we hypothesize that nitrous oxide can induce neuronal release of specific opioid peptides and that this drug action might be associated with the analgesic effect of nitrous oxide. Our specific aim is to submit this hypothesis to testing by a set of postulates designed to verify an opiate involvement in a physiological or pharmacological process. These tests will involve 1. antagonism by naloxone, 2. non-antagonism by (+)-naloxone, 3. cross-tolerance with morphine, 4. potentiation by inhibitors of enkephalin metabolism, and 5. demonstration of release of opioid peptides. These tests will be conducted, using nitrous oxide-induced analgesia in behavioral models and nitrous oxide-induced changes in perfusate ME-like immunoreactivity in anesthetized and conscious centrally-perfused rats. Our methods will include the rat tail flick test, the rat hot plate test, ventricular-cisternal perfusion, intrathecal perfusion, radioimmunoassay and high performance liquid chromatography separation or assay of opioid peptides. The long-term objectives of this research are to systemically analyze the drug actions and effects of nitrous oxide and eventually other general anesthetic drugs as well. The findings of this research should contribute to our understanding and knowledge of the pharmacology of nitrous oxide.
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0.951 |
1990 |
Quock, Raymond Mark |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Nitrous Oxide Conscious Sedation--Anxioysis @ University of Illinois At Chicago
Nitrous oxide is widely used for production of conscious sedation in clinical dentistry. This clinical application of low concentrations of nitrous oxide specifically for reduction of anxiety is unique to dentistry. Nitrous oxide also possesses prominent analgesic and weak anesthetic properties that have been widely studied. However, its anxiolytic effect has not been well investigate and the underlying mechanism(s) of action remain(s) unknown. Recent research suggests that an apparent anxiolytic effect of nitrous oxide is demonstrable in the mouse staircase test, a relatively new anxiety paradigm. This application proposes pilot experiments to determine the feasibility of future basic research into the mechanism of anxiolytic effect of nitrous oxide. The goals of this proposed research are to study 2 established and validated experimental paradigms (the social interaction test and the defensive burying test in rats): (1) a concentration-dependent anxiolytic effect of nitrous oxide and comparison with chlordiazepoxide (an anxiolytic standard) and morphine (an analgesic standard); and (2) sensitivity of the effects of these 3 drug challenges (nitrous oxide, chlordiazepoxide and morphine) to interaction with opioid and benzodiazepine receptor blockers. Carried to a successful conclusion, this proposed research will make possible further and more sophisticated investigations for characterization of the anxiolytic effect of nitrous oxide and elucidation of its mechanism(s) of action. The long term objective of this research is to continue a systematic analysis of the pharmacological properties of nitrous oxide. The findings of such research should advance our understanding of the pharmacology of nitrous oxide and contribute to more efficacious or judicious clinical use of nitrous oxide in dentistry and medicine.
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0.945 |
1991 — 1993 |
Quock, Raymond Mark |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Nitrous Oxide and Endogenous Opioid Systems @ University of Illinois At Chicago
Nitrous oxide is a gaseous pharmacological agent with a broad range of clinical applications in medicine and dentistry. Despite the use of nitrous oxide as a clinical analgesic agent, its mechanism of action remains somewhat nebulous. Recent research conducted in our laboratory and elsewhere implicates an interaction of subanesthetic concentrations of nitrous oxide with endogenous opioid systems. Based on various experimental findings, we hypothesize that nitrous oxide analgesia might result from drug-stimulated neuronal release of specific endogenous opioid peptides (EOPs) with subsequent activation of central analgesia-mediating opioid receptors. Over the past several years, research efforts in our laboratory have been devoted to further eluci- dation of this opioid connection in nitrous oxide analgesia. The objectives of this proposed research are to: (1) identify the subtype(s) and location(s) of central opioid receptors that mediate nitrous oxide analgesia; (2) quantify and identify the increased EOPs in artificial cerebrospinal fluid perfusate collected from both anesthetized and conscious, centrally perfused rats exposed to nitrous oxide; and (3) correlate the degree of nitrous oxide analgesia with changes in regional brain and spinal cord levels of EOPs. Towards these ends, both biological and chemical approaches will be employed. The biological approaches will include rat stereotaxic surgery and intra- cerebroventricular/intrathecal/intracerebral microinjection technique, and analgesia testing (hot plate test). The chemical approaches will include radioimmunoassay for EOPs in ventricular-cisternal/intrathecal perfusate and nervous tissues of rats !exposed to nitrous oxide, and fractionation by high performance liquid chromatography (HPLC) for EOPs from perfusate and tissue samples from rats exposed to nitrous oxide. Other parameters to be monitored include inspired anesthetic agents, body temperature, blood pressure and blood chemistry. The long term goal of this continuing research is to systematically analyze the opioid nature of the drug actions and drug effects of nitrous oxide. The findings of this research should advance our understanding and knowledge of the pharmacology of nitrous oxide, which appears to be a unique and useful therapeutic and investigative opioid agent. This work should contribute to more efficacious or judicious clinical use of nitrous oxide in medicine and dentistry.
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0.945 |
1997 — 1999 |
Quock, Raymond Mark |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Control of Responsiveness to N20 Antiociception @ University of Illinois At Chicago
DESCRIPTION: (Applicant's Abstract) The mechanism of nitrous oxide (N20) analgesia remains uncertain, although research in mice has implicated an involvement of both kappa-opioid receptors and nitric oxide (N0). Differential responsiveness inbred C57BL/6 and DBA/2 mice to N20 antinociception has focused attention on the role of N0 in N20 action, and results of preliminary studies suggest a difference in N0 function between these strains. C57BL/6 mice are responsive to N20 antinociception and show increased N0 synthase (NOS) activity after N20 exposure, but DBA/2 mice are poorly responsive and show no such increase in NOS activity. The reduced sensitivity to N20 antinociception persists in certain BXD recombinant inbred (Rl) strains derived from the C57BL/6 and DBA/2 progenitors. Analysis of the BXD Rl data has identified provisional quantitative trait loci (QTL) or chromosome sites containing alleles that influence antinociceptive responsiveness to N20. The specific aims of this research are to: (1) compare the role of NO in N20 antinociception in the progenitors by determining how the N20 response is affected by selective inhibition of neuronal vs. endothelial NOS in C57BL/6 mice and by NO loading in DBA/2 mice; (2) compare NOS function in C57BL/6 and DBA/2 mice by measuring conversion of [14C]L-arginine to [14C]L-citrulline in brain regions and spinal cords of naive and N20-exposed C57BL/6 and DBA/2 mice; (3) compare the role of NO in N20-induced neuronal release of opioid peptides by determining the influence of NOS inhibition on N20 protection against alkylation of opioid receptors; (4) identify QTL associated with N20 antinociception by determining responsiveness of B6D2F2 mice to N20 and genotyping using a whole genome scan; and (5) ascertain the correlation between antinociceptive responsiveness of B6D2F2 mice and their regional brain and spinal cord NOS activity levels. Methods to be utilized will include the following: antinociceptive testing; NOS assay; opioid radioligand binding; and PCR amplification of polymorphic genetic markers. The results of this research will determine why C57BL/6 and DBA/2 mice respond differently to N20 and help to identify specific genes and the roles played by NOS and NO in analgesic and anesthetic drug effects. This work will also contribute better understanding of the variability in human responsiveness to N20.
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1 |
1997 — 1999 |
Quock, Raymond Mark |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Signaling Pathway For Benzodiazepine Induced Behaviors @ University of Illinois At Chicago
DESCRIPTION: (Applicant's Abstract) Benzodiazepines are among the most widely prescribed medications in the world, While benzodazepines are both clinically efficacious and safe, there are nonetheless concerns about whether inappropriate or over prescription of these drugs contributes to abuse and dependence. The site(s) and mechanism of behavioral actions of benzodiazepines in the central nervous system (CNS) remain uncertain. The proposed research is designed to test a working hypothesis that behaviors initiated by drug action at the benzodiazepine/y aminobutyric acidA (GABAA) receptor complex are mediated by a nitric oxide (NO)/cyclic GMP (cGMP)/protein kinase G (PKG) signaling pathway, i.e., stimulation of the benzodiazepine/GABAA receptor complex activates NO synthase (NOS) to produce NO, which activates soluble guanylyl cyclase (GC-S) to produce cGMP, which, in turn, activates a cyclic GMP-dependent protein kinase, leading to the behavioral effects. This will be accomplished by comparing the behavioral effects of the benzodiazepine chlordiazepoxide, the GABAA agonist 4,5,6,7-tetrahydro-isoxazolo[5,4-c]pyridin-3-ol (THIP) and nitrous oxide, another drug of abuse that appears to work at least in part through benzodiazepine/GABAA receptors, in mice following pharmacological manipulation of NOS, NO, guanylyl cyclase, cyclic GMP, and PKG in the CNS. Drug pretreatments will result in reduction in brain NO by inhibition of NOS, restoration of NO in NOS-inhibited brain, inhibition of NO action by an NO scavenger, reduction in brain cGMP by inhibition of GC-S, increase in brain cGMP by inhibition of cGMP degradation, and selective inhibition of protein kinase G (PKG). Other drug challenges will include NO-donors, dibutyryl cGMP and PKG-activators. Methods to be used in this research include behavioral testing in mice (elevated plus-maze and light/dark exploration), central microinjection of pretreatment drugs, and assays to measure cGMP and NOS or PKG enzyme activities. The purpose of the proposed studies is to identify the signaling pathway that mediates benzodiazepine-induced behaviors and provide a progressively more complete understanding, at the molecular level, of the pharmacological and neurochemical mechanisms underlying acute benzodiazepine-induced behaviors.
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1 |
2007 |
Quock, Raymond Mark |
R15Activity Code Description: Supports small-scale research projects at educational institutions that provide baccalaureate or advanced degrees for a significant number of the Nation’s research scientists but that have not been major recipients of NIH support. The goals of the program are to (1) support meritorious research, (2) expose students to research, and (3) strengthen the research environment of the institution. Awards provide limited Direct Costs, plus applicable F&A costs, for periods not to exceed 36 months. This activity code uses multi-year funding authority; however, OER approval is NOT needed prior to an IC using this activity code. |
No Mechanisms in N2o Antinociception in Inbred Mice @ Washington State University
[unreadable] DESCRIPTION (provided by applicant): Lack of understanding of the role of neuronal nitric oxide synthase (nNOS) and nitric oxide ( problem because, without it, researchers may be overlooking alternative targets that might be exploited in pain management. Our long-term goal is to increase the efficacy of clinical management of pain. The objective in this application is to identify the role of induced antinociception in mice. Our central hypothesis is that the poor responsiveness of the DBA/2 strain to N2O might be due to an anomaly in the enzyme, cofactor, promoter strength/response or post-translational modification) that is involved in N2O-induced antinociception. By taking advantage of the differential responsiveness of two inbred strains (C5BL/6 and DBA/2) to N2O, this research will garner increased knowledge of the role of to N2O. The Specific Aims of the proposed research include the following: 1) determination of the role of spinal and supraspinal N2O-induced antinociception in NOS knockout and knockdown mice; 2) establishing the dose-response relationship between drugs that increase brain induced antinociception in C57BL/6 and DBA/2 mice; and 3) measurement and comparison of the effects of N2O exposure on mice. These goals will be attained by pharmacological, neurochemical and molecular biology methods. This contribution will be significant because it is expected that new targets for therapeutic intervention will be identified and development of new drugs that can optimize pain management will be stimulated. Our long-term goal is to increase the effectiveness of clinical management of pain. The rationale for the proposed research is to identify and localize new targets for development of drugs (and possibly non-drug) means that can be used to optimize pain management. [unreadable] [unreadable] [unreadable]
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1 |
2012 — 2013 |
Quock, Raymond Mark |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Hyperbaric Oxygen: a Novel Approach to Treatment of Chronic Pain @ Washington State University
DESCRIPTION (provided by applicant): This is a revision of R21 AT007222-01 to study the mechanism of action of hyperbaric oxygen (HBO2) in producing pain relief. Earlier studies demonstrated an antinociceptive effect of HBO2 in models of acute pain, including an unparalleled weeks-long antinociceptive effect, the development of which was prevented by inhibition of nitric oxide (NO) production at the time of HBO2 treatment. More recent studies have shown that HBO2 treatment produced an antiallodynic effect in rats with paclitaxel-induced neuropathic pain that lasted for up to four weeks following HBO2 treatment. The role of NO in the genesis of such a long-acting effect of HBO2 is unique and needs to be explored and exploited for clinical management of pain. Our long-term goal is to identify the pathway that is activated by HBO2 through NO and mediates a very long-lasting relief of pain. The objective in this R21 proposal is to determine the possible relationship between HBO2-induced changes in NO function and its antiallodynic effect. Our central hypothesis is that HBO2 stimulates the prolonged production of NO, which, in turn, activates a descending pathway involving opioid, GABA and 5HT1A mechanisms that may be responsible for an antiallodynic effect of unusually long duration. Our specific aims are to: 1) characterize the time course and underlying mechanisms of the antiallodynic response to single and repeated HBO2 treatments; and 2) characterize HBO2-induced changes in nNOS expression and determine the anatomical relationship between brainstem nNOS expression, GABA and descending serotonergic antinociceptive neurons. Pharmacological, immunohistochemical and molecular approaches will be employed in achieving these specific aims. The approach is innovative because it will elucidate the mechanism of analgesic action of HBO2, a treatment modality that has not typically been used for pain relief. The significance of the proposed research is that it will provide a scientific basis for clinical use of HBO2 in chronic pain management and identify the responsible neural pathway so that it may be targeted for small molecule development to activate the same mechanisms to produce extremely long-lasting relief of chronic pain. PUBLIC HEALTH RELEVANCE: The brain is endowed with endogenous pain-modulating systems that have not been optimally exploited in the management of clinical pain. By identifying factors that contribute to how hyperbaric oxygen activates these endogenous mechanisms, this research will advance the field of pain management identifying molecular targets to cause a long-lasting activation of endogenous pain-modulating systems.
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