Stein C, Pflüger M, Yassouridis A, Hoelzl J, Lehrberger K, Welte C, Hassan A H
Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland 21287-8711, USA.
J Clin Invest. 1996 Aug 1;98(3):793-9. doi: 10.1172/JCI118852.
Pain treatment with centrally acting opiates is limited by tolerance. Tolerance is a decreasing effect of a drug with prolonged administration of that drug or of a related (e.g., endogenous) compound acting at the same receptor. This is often associated with a downregulation of receptors. In peripheral inflamed tissue, both locally expressed opioid peptides and morphine can produce powerful analgesia mediated by similar populations of opioid receptors. We hypothesized that the chronic presence of endogenous opioids in inflamed joints might convey downregulation of peripheral opioid receptors and tolerance to the analgesic effects of intraarticular morphine. We assessed these effects after arthroscopic surgery in patients with and without histologically verified synovial cellular infiltration, and we examined synovial opioid peptides and opioid receptors by immunocytochemistry and autoradiography, respectively. We found that, despite an abundance of opioid-containing cells in pronounced synovitis, morphine is at least as effective as in patients without such cellular infiltrations, and there is no major downregulation of peripheral opioid receptors. Thus, opioids expressed in inflamed tissue do not produce tolerance to peripheral morphine analgesia. Tolerance may be less pronounced for peripherally than for centrally acting opioids, which provides a promising perspective for the treatment of chronic pain in arthritis and other inflammatory conditions.
中枢作用阿片类药物的疼痛治疗受耐受性限制。耐受性是指药物长期给药或作用于同一受体的相关（如内源性）化合物给药后药物效应降低。这通常与受体下调有关。在周围炎症组织中，局部表达的阿片肽和吗啡均可通过相似的阿片受体群体产生强效镇痛作用。我们推测，炎症关节中内源性阿片类物质的长期存在可能导致周围阿片受体下调以及对关节内吗啡镇痛作用产生耐受性。我们在有和没有组织学证实的滑膜细胞浸润的患者接受关节镜手术后评估了这些效应，并分别通过免疫细胞化学和放射自显影检查了滑膜阿片肽和阿片受体。我们发现，尽管在明显的滑膜炎中有大量含阿片类物质的细胞，但吗啡的效果至少与没有这种细胞浸润的患者一样好，并且周围阿片受体没有明显下调。因此，炎症组织中表达的阿片类物质不会产生对周围吗啡镇痛的耐受性。与中枢作用的阿片类药物相比，周围作用的阿片类药物的耐受性可能不那么明显，这为治疗关节炎和其他炎症性疾病中的慢性疼痛提供了一个有前景的视角。
