Sanderson K, Nyberg F, Khalil Z
Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Inflamm Res. 1998 Feb;47(2):49-55. doi: 10.1007/s000110050266.
Sensory nerves mediate peripheral inflammation via the release of sensory peptides at the site of tissue injury. Using a blister model of inflammation, we have previously documented that endogenous opioids modulate chronic but not acute inflammation. Hemorphins are nonclassical opioid peptides found in the region of the beta-chain of hemoglobin (Hb). The heptapeptide hemorphin-7 is identical with residues 35-41 of the beta-chain of the human Hb. The aim of this study was to examine the effect of hemorphin-7 on the inflammatory response in acute and chronic injury models.
We have used a vacuum-induced blister model in the footpad of anaesthetized rats to induce an inflammatory response in naive skin by (a) electrical stimulation (ES) of the distal end of the cut sciatic nerve at 20 V, 5 Hz, 2 ms for 1 min or (b) superfusion of sensory peptides; substance P (SP) or calcitonin gene related peptide (CGRP) over the blister base. In addition, we examined the effect of hemorphin-7 on the inflammatory response to SP induced in a previously injured but healed skin site (recurrent injury model) and in denervated skin site due to chronic nerve lesion (chronic injury model).
The results showed that prior and concomitant perfusion of hemorphin-7 over the blister base inhibited the acute inflammatory response to ES of the sciatic nerve at C-fibre strength in a dose-dependent manner. Significant inhibition was achieved at 20 and 200 microM concentration of hemorphin-7. When hemorphin-7 (20 microM) was perfused prior to and together with SP or CGRP (both at 1 microM), over the base of acutely induced blister in naive skin, it significantly reduced the inflammatory response to SP (both plasma extravasation and vasodilatation), but was without effect on the vasodilatation response to CGRP. Naloxone, the general opioid antagonist at (1 mg/kg i.v.) reversed the inhibitory effect of hemorphin-7 on the inflammatory response to SP. On the other hand, hemorphin-7 had no effect on the inflammatory response to SP in the recurrent injury or the chronic injury models.
The results of this study suggest that hemorphins might play a role in inhibiting the inflammatory response in acute, but not in recurrent or chronic injury conditions. Evidence is also provided that the modulatory inhibitory effect of hemorphin-7 is mediated via activation of opioid receptor(s). The significance of this study in conjunction with our previous work, is that it raises the possibility that different endogenous inhibitory mechanisms may operate under different injury conditions - endogenous hemorphins and opioids may modulate acute and chronic inflammation, respectively.
感觉神经通过在组织损伤部位释放感觉肽来介导外周炎症。我们之前利用炎症水疱模型证明，内源性阿片类物质可调节慢性炎症，但对急性炎症无此作用。血啡肽是在血红蛋白（Hb）β链区域发现的非经典阿片肽。七肽血啡肽-7与人Hbβ链的35-41位残基相同。本研究旨在探讨血啡肽-7在急性和慢性损伤模型中对炎症反应的影响。
我们采用麻醉大鼠足垫的真空诱导水疱模型，通过以下方式在未损伤皮肤中诱导炎症反应：（a）以20V、5Hz、2ms的强度电刺激切断的坐骨神经远端1分钟；（b）在水疱底部灌注感觉肽，即P物质（SP）或降钙素基因相关肽（CGRP）。此外，我们还研究了血啡肽-7对先前损伤但已愈合皮肤部位（复发性损伤模型）和慢性神经损伤所致失神经皮肤部位（慢性损伤模型）中SP诱导的炎症反应的影响。
结果显示，在水疱底部预先或同时灌注血啡肽-7，可剂量依赖性地抑制坐骨神经以C纤维强度电刺激引起的急性炎症反应。血啡肽-7浓度为20和200μM时可实现显著抑制。当在未损伤皮肤急性诱导水疱底部预先及同时灌注血啡肽-7（20μM）与SP或CGRP（均为1μM）时，血啡肽-７可显著减轻对SP的炎症反应（包括血浆外渗和血管舒张），但对CGRP引起的血管舒张反应无影响。阿片类物质通用拮抗剂纳洛酮（1mg/kg静脉注射）可逆转血啡肽-7对SP炎症反应的抑制作用。另一方面，血啡肽-7对复发性损伤或慢性损伤模型中SP诱导的炎症反应无影响。
本研究结果提示，血啡肽可能在抑制急性炎症反应中发挥作用，但在复发性或慢性损伤情况下则不然。同时也证明血啡肽-7的调节性抑制作用是通过阿片受体激活介导的。结合我们之前的工作，本研究的意义在于，它提出了一种可能性，即不同的内源性抑制机制可能在不同的损伤条件下起作用——内源性血啡肽和阿片类物质可能分别调节急性和慢性炎症。
