Hyperbaric Oxygen: A Novel Approach to Treatment of Chronic Pain

高压氧：治疗慢性疼痛的新方法

• 批准号: 8430875
• 负责人: RAYMOND MARK QUOCK
• 金额: $ 22.89万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8430875
• 关键词: Acute Pain; American; Analgesics; Brain; Brain Stem; Clinical; Clinical Management; Data; Development; Dura Mater; Environment; Goals; Hyperbaric Oxygen; Immunoblotting; Immunohistochemistry; Investigation; Laboratories; Mediating; Medical; Messenger RNA; Modality; Modeling; Molecular; Molecular Target; Neural Pathways; Neurons; Nitric Oxide; Opioid; Paclitaxel; Pain; Pain management; Pathway interactions; Patients; Population; Production; Proteins; Qualifying; Rattus; Research; Role; Source; Spinal; System; Tactile; Techniques; Testing; Time; Visit; Work; allodynia; base; chronic neuropathic pain; chronic pain; design; experience; gamma-Aminobutyric Acid; innovation; interest; midbrain central gray substance; mouse model; novel strategies; painful neuropathy; prevent; receptor; response; small molecule; success

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.

描述（由申请人提供）：这是R21 AT007222-01的修订，旨在研究高压氧（HBO2）在产生疼痛缓解中的作用机制。早期的研究表明，HBO2在急性疼痛模型中具有抗伤害性作用，包括无与伦比的长达数周的抗伤害性作用，这种作用的发展是通过抑制HBO2治疗时一氧化氮（NO）的产生而阻止的。最近的研究表明，HBO2治疗对紫杉醇诱导的神经性疼痛大鼠产生抗异动作用，这种疼痛在HBO2治疗后持续长达四周。一氧化氮在HBO2产生如此长效效应中的作用是独特的，需要在疼痛的临床治疗中加以探索和利用。我们的长期目标是确定HBO2通过NO激活并介导非常持久的疼痛缓解的途径。本R21提案的目的是确定hbo2诱导的NO功能变化与其抗异动作用之间的可能关系。我们的中心假设是HBO2刺激一氧化氮的长时间产生，而一氧化氮的长时间产生又激活了一条涉及阿片、GABA和5HT1A机制的下行通路，这可能是导致异常长时间抗异动作用的原因。我们的具体目标是：1)表征单次和重复HBO2治疗的抗allodyresponse的时间过程和潜在机制；2)表征hbo2诱导的nNOS表达变化，确定脑干nNOS表达、GABA和血清素能抗感觉神经元下降之间的解剖关系。药理学、免疫组织化学和分子方法将被用于实现这些特定的目标。该方法具有创新性，因为它将阐明HBO2的镇痛作用机制，这是一种通常不用于缓解疼痛的治疗方式。本研究的意义在于为HBO2在慢性疼痛治疗中的临床应用提供科学依据，并确定相关的神经通路，从而有针对性地进行小分子开发，激活相同的机制，产生极持久的慢性疼痛缓解。