Relative contributions of peripheral versus supraspinal or spinal opioid receptors to the antinociception of systemic opioids
Relative contributions of peripheral versus supraspinal or spinal opioid receptors to the antinociception of systemic opioids
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DOI：
10.1002/j.1532-2149.2011.00070.x
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发表时间：
2012-05-01
影响因子：
3.6
通讯作者：
Schaefer, M.
中科院分区：
文献类型：
--
作者：
Khalefa, B. I.;Shaqura, M.;Schaefer, M.
脊髓上、脊髓或外周MU-阿片受体(MORS)在全身性中枢穿透阿片与外周受限阿片的整体抗伤害作用中的作用尚未得到彻底的研究。因此，我们检测了不同剂量足底注射后完全弗氏佐剂性后足炎的Wistar大鼠的足爪压力阈值。以及静脉注射(Iv)。芬太尼(6.25-50毫克/公斤)、吗啡(1-7.5毫克/公斤)或氯哌丁胺(1-7.5毫克/公斤)。侧脑室(I.C.V.)、鞘内(I.T.)对阿片受体激动剂的拮抗作用或i.pl。纳洛酮-甲碘化物(NLXM)揭示了脊髓上、脊髓和外周MOR对整体抗伤害效应的相对贡献。同时，通过放射配基结合来评估这三个水平的疼痛传递的MOR密度。与静脉注射芬太尼和吗啡相比，静脉注射芬太尼和吗啡的抗伤害性作用强2到3倍，而且持续时间更长，但外周限制性氯哌丁胺不起作用。行政管理。I.C.V.，但不是I.Pl。NLXM显著拮抗芬太尼和吗啡的抗伤害性作用70-80%，而I.T.NLXM使其降低了20-30%。相反，静脉注射氯哌丁胺的抗伤害性作用被I.Pl取消。但不是通过I.C.V.或I.T.。NLXM。同时，在棘上感觉神经元和脊髓感觉神经元中检测到的MOR密度分别是外周感觉神经元的32倍和6倍。综上所述，与脊髓上阿片受体和脊髓阿片受体相比，外周阿片受体对全身芬太尼和吗啡在炎性疼痛中的抗伤害性作用并不显著。他们静脉给药的抗伤害性优于静脉注射和静脉注射。洛哌丁胺，仅通过外周MOR起作用。这些发现可能会指导新型外周限制性阿片类药物的未来发展。
The contribution of supraspinal, spinal or peripheral mu-opioid receptors (MORs) to the overall antinociception of systemic centrally penetrating versus peripherally restricted opioids has not been thoroughly investigated. Therefore, we examined paw pressure thresholds in Wistar rats with complete Freund's adjuvant hindpaw inflammation following different doses of intraplantar (i.pl.) as well as intravenous (i.v.) fentanyl (6.25-50 mu g/kg), morphine (1-7.5 mg/kg) or loperamide (1-7.5 mg/kg). Antagonism of the i. v. mu-opioid agonists by intracerebroventricular (i. c. v.), intrathecal (i.t.) or i.pl. naloxone-methiodide (NLXM) revealed the relative contributions of supraspinal, spinal and peripheral MOR to the overall antinociceptive effects. In parallel, the MOR density at these three levels of pain transmission was assessed by radioligand binding. Antinociceptive effects of i. v. fentanyl and morphine, but not of the peripherally restricted loperamide were two-to threefold greater and longer lasting compared with their i.pl. administration. I. c. v. but not i. pl. NLXM significantly antagonized fentanyl's and morphine's antinociception by 70-80%, whereas i.t. NLXM reduced it by 20-30%. In contrast, antinociception of i. v. loperamide was abolished by i. pl. but not by i. c. v. or i.t. NLXM. In parallel, a respective 32- and sixfold higher MOR density in supraspinal and spinal versus peripheral sensory neurons was detected. In conclusion, in comparison with supraspinal and spinal opioid receptors, peripheral opioid receptors do not significantly contribute to the antinociception of systemic fentanyl and morphine during inflammatory pain. Antinociception of their i. v. administration was superior over both i. v and i. pl. loperamide, acting exclusively via peripheral MOR. These findings may guide the future development of novel peripherally restricted opioids.