PERIPHERAL OPIOID ANALGESIA--BASIC MECHANISMS & CLINICAL IMPLICATIONS

外周阿片受体的激活抑制炎症疼痛。 我们研究了阿片受体对交感神经系统的作用， 节后神经元（SPN）与初级传入神经元（PAN）， 外周阿片镇痛在后爪炎症大鼠中， （足底）注射μ-、_-和k-阿片样物质激动剂产生的剂量- 依赖性镇痛作用。辣椒素预处理可减弱这些 效果比用6-羟基多巴胺预处理高得多， 这表明PAN和SPN上存在阿片受体，但 前者对外周阿片类镇痛的作用大于 后者阿片肽在常驻免疫细胞内合成 发炎的组织在被释放后，它们也会激活 外周阿片受体作为内源性配体，并产生类似 镇痛作用我们研究了阿片类药物的产生和释放， 体外免疫细胞POMC mRNA水平在免疫细胞中较高， 炎症与非炎症腘淋巴结（LN），而β- 内啡肽含量较低，表明免疫细胞释放了 当它们从发炎的爪子返回时， 引流LN。用促肾上腺皮质激素刺激免疫细胞- 释放因子（CRF）和白细胞介素-1（IL-1）触发β- 内啡肽以受体特异性和钙依赖性的方式。 足底注射CRF和IL-1产生强镇痛作用 在体内通过从免疫细胞释放阿片肽来介导。 用CRF反义物抑制炎症组织中的CRF合成 寡脱氧核苷酸消除内源性局部阿片样物质镇痛。这些 研究结果表明，免疫系统在 疼痛控制这对理解 免疫抑制条件下疼痛的病理生理学， 艾滋病此外，这些研究为发展提供了动力， 新型化合物， 专门（原型已经由几个制药公司开发， 公司），或引发局部内源性阿片肽的释放 从免疫细胞中分离出来，一个原型就是CRF的优点 这种治疗疼痛的外围方法缺乏 中枢阿片副作用，如欣快、成瘾或依赖。 这可能会导致减少使用和可用的常规药物， 中枢作用类阿片，从而减少类阿片滥用的流行率 以及随之而来的问题，如艾滋病。

Activation of peripheral opioid receptors inhibits pain in inflammation. We examined the contribution of opioid receptors on sympathetic postganglionic neurons (SPN) versus primary afferent neurons (PAN) to peripheral opioid analgesia. In rats with hindpaw inflammation, the local (intraplantar) injection of mu-, _- and k-opioid agonists produced dose- dependent analgesic effects. Pretreatment with capsaicin attenuated these effects to a much higher degree than pretreatment with 6-hydroxydopamine, suggesting that opioid receptors are present on PAN and SPN, but that the former contribute to a greater extent to peripheral opioid analgesia than the latter. Opioid peptides are synthesized within resident immune cells of the inflamed tissue. After being released they also activate peripheral opioid receptors as endogenous ligands, and produce similar analgesic effects. We investigated opioid production and release from immune cells in vitro. POMC mRNA levels were higher in immune cells of inflamed versus noninflamed popliteal lymph nodes (LN), whereas the beta- endorphin content was lower, suggesting that immune cells have released most of their beta-endorphin when they return from the inflamed paw to the draining LN. Stimulation of immune cells with corticotrophin- releasing factor (CRF) and interleukin-1 (IL-1) triggers release of beta- endorphin in a receptor specific and calcium dependent manner. Intraplantar injection of CRF and IL-1 produces potent analgesic effects in vivo mediated by a release of opioid peptides from immune cells. Inhibition of CRF synthesis in inflamed tissue with a CRF antisense oligodeoxynucleotide abolishes endogenous local opioid analgesia. These findings demonstrate that the immune system plays an important role in pain control. This has wide ranging implications for the understanding of the pathophysiology of pain in immunosuppressed conditions such as AIDS. In addition, these studies provide an incentive for the development of novel compounds that either target peripheral opioid receptors exclusively (prototypes have been developed by several pharmaceutical companies), or that trigger a release of local endogenous opioid peptides from immune cells, a prototype of which would be CRF. The advantage of such a peripheral approach for the treatment of pain is the lack of central opioid side effects such as euphoria, addiction or dependence. This may lead to a reduction of the use and availability of conventional centrally acting opioids and, thus, reduce the prevalence of opioid abuse and ensuing problems such as AIDS.