Hyperbaric Oxygen: A Novel Approach to Treatment of Chronic Pain

描述（由申请方提供）：这是R21 AT 007222 -01的修订版，旨在研究高压氧（HBO 2）缓解疼痛的作用机制。早期的研究表明，HBO 2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，其发展通过在HBO 2治疗时抑制一氧化氮（NO）的产生来阻止。最近的研究表明，HBO 2治疗对紫杉醇诱导的神经性疼痛大鼠产生抗异常性疼痛作用，该作用在HBO 2治疗后持续长达四周。NO在HBO 2的这种长效作用的发生中的作用是独特的，需要探索和开发用于疼痛的临床管理。我们的长期目标是确定由HBO 2通过NO激活并介导非常持久的疼痛缓解的途径。本研究的目的是确定HBO 2诱导的NO功能变化与其抗异常性疼痛作用之间的可能关系。我们的中心假设是HBO 2刺激NO的长时间产生，这反过来又激活了一条涉及阿片类药物、GABA和5 HT 1A机制的下行通路，这可能是持续时间异常长的抗异常性疼痛作用的原因。我们的具体目标是：1）表征对单次和重复HBO 2治疗的抗异常性疼痛反应的时间过程和潜在机制;和2）表征HBO 2诱导的nNOS表达的变化，并确定脑干nNOS表达、GABA和下行性多巴胺能抗伤害感受神经元之间的解剖学关系。将采用药理学、免疫组织化学和分子方法来实现这些特定目标。该方法是创新的，因为它将阐明HBO 2的镇痛作用机制，HBO 2是一种通常不用于缓解疼痛的治疗方式。这项研究的意义在于，它将为HBO 2在慢性疼痛管理中的临床应用提供科学依据，并确定负责的神经通路，以便它可以被小分子开发所针对，以激活相同的机制，从而产生极其持久的慢性疼痛缓解。

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.