σ1 受体对周围 μ 阿片样物质镇痛作用的调制。
Modulation of peripheral μ-opioid analgesia by σ1 receptors.
机构信息
Departments of Pharmacology (C.S.-F., A.M.-G., R.G.-C., F.R.N., L.R., A.A.-C., J.M.B., E.J.C.) and Physiology (R.M.), School of Medicine, University of Granada, Granada, Spain; Institute of Neuroscience, Biomedical Research Center, University of Granada, Granada, Spain (C.S.-F., R.G.-C., F.R.N., R.M., J.M.B., J.M.E., E.J.C.); Animal Behavior Research Unit, Scientific Instrumentation Center, University of Granada, Granada, Spain (J.M.E.); and Drug Discovery and Preclinical Development, Barcelona, Spain (B.F.-P., M.M.).
出版信息
J Pharmacol Exp Ther. 2014 Jan;348(1):32-45. doi: 10.1124/jpet.113.208272. Epub 2013 Oct 23.
We evaluated the effects of σ1-receptor inhibition on μ-opioid-induced mechanical antinociception and constipation. σ1-Knockout mice exhibited marked mechanical antinociception in response to several μ-opioid analgesics (fentanyl, oxycodone, morphine, buprenorphine, and tramadol) at systemic (subcutaneous) doses that were inactive in wild-type mice and even unmasked the antinociceptive effects of the peripheral μ-opioid agonist loperamide. Likewise, systemic (subcutaneous) or local (intraplantar) treatment of wild-type mice with the selective σ1 antagonists BD-1063 [1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride] or S1RA [4-[2-[[5-methyl-1-(2-naphthalenyl)1H-pyrazol-3-yl]oxy]ethyl] morpholine hydrochloride] potentiated μ-opioid antinociception; these effects were fully reversed by the σ1 agonist PRE-084 [2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate) hydrochloride], showing the selectivity of the pharmacological approach. The μ-opioid antinociception potentiated by σ1 inhibition (by σ1-receptor knockout or σ1-pharmacological antagonism) was more sensitive to the peripherally restricted opioid antagonist naloxone methiodide than opioid antinociception under normal conditions, indicating a key role for peripheral opioid receptors in the enhanced antinociception. Direct interaction between the opioid drugs and σ1 receptor cannot account for our results, since the former lacked affinity for σ1 receptors (labeled with (3)H-pentazocine). A peripheral role for σ1 receptors was also supported by their higher density (Western blot results) in peripheral nervous tissue (dorsal root ganglia) than in several central areas involved in opioid antinociception (dorsal spinal cord, basolateral amygdala, periaqueductal gray, and rostroventral medulla). In contrast to its effects on nociception, σ1-receptor inhibition did not alter fentanyl- or loperamide-induced constipation, a peripherally mediated nonanalgesic opioid effect. Therefore, σ1-receptor inhibition may be used as a systemic or local adjuvant to enhance peripheral μ-opioid analgesia without affecting opioid-induced constipation.
我们评估了 σ1 受体抑制对 μ 阿片类药物诱导的机械性镇痛和便秘的影响。σ1 敲除小鼠对几种 μ 阿片类镇痛药（芬太尼、羟考酮、吗啡、丁丙诺啡和曲马多）表现出明显的机械性镇痛作用，这些药物在野生型小鼠中的系统（皮下）剂量无效，甚至揭示了外周 μ 阿片类激动剂洛哌丁胺的镇痛作用。同样，选择性 σ1 拮抗剂 BD-1063[1-[2-(3,4-二氯苯基)乙基]-4-甲基哌嗪二盐酸盐]或 S1RA[4-[2-[[5-甲基-1-(2-萘基)1H-吡唑-3-基]氧基]乙基]吗啉盐酸盐]的全身（皮下）或局部（足底内）治疗增强了 μ 阿片类药物的镇痛作用；这些作用被 σ1 激动剂 PRE-084[2-(4-吗啉乙基)-1-苯基环己烷羧酸盐酸盐]完全逆转，表明了这种药理学方法的选择性。由 σ1 抑制（通过 σ1 受体敲除或 σ1 药理学拮抗）增强的 μ 阿片类药物镇痛作用对周围受限的阿片类拮抗剂纳洛酮甲碘化物比正常情况下的阿片类药物镇痛作用更敏感，表明外周阿片受体在增强的镇痛作用中起着关键作用。阿片类药物和 σ1 受体之间的直接相互作用不能解释我们的结果，因为前者缺乏与 σ1 受体（用 (3)H-戊烷嗪标记）的亲和力。σ1 受体在外周组织（背根神经节）中的密度（Western blot 结果）高于参与阿片类药物镇痛的几个中枢区域（背侧脊髓、基底外侧杏仁核、导水管周围灰质和头腹侧延髓），这也支持了其在外周的作用。与镇痛作用相反，σ1 受体抑制不会改变芬太尼或洛哌丁胺引起的便秘，这是一种外周介导的非阿片类药物作用。因此，σ1 受体抑制可作为一种全身性或局部辅助剂，增强外周 μ 阿片类药物镇痛作用，而不影响阿片类药物引起的便秘。
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