Labuz Dominika, Mousa Shaaban A, Schäfer Michael, Stein Christoph, Machelska Halina
Klinik für Anaesthesiologie und operative Intensivmedizin, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany.
Brain Res. 2007 Jul 30;1160:30-8. doi: 10.1016/j.brainres.2007.05.049. Epub 2007 Jun 2.
Opioid effects are mediated by central and peripheral opioid receptors. Here we examine the relative contribution of each receptor population to antinociception elicited by systemically administered centrally penetrating opioids, and by loperamide (a peripherally restricted opioid). Nociception (abdominal writhes) was induced by intraperitoneally (i.p.) injected 0.6% acetic acid in mice. We analyzed opioid receptor expression in peritoneum by immunohistochemistry, antinociception after i.p. injected agonists at mu (morphine, loperamide)-, delta (SNC80)- and kappa (U50488)-receptors, and its reversibility by subcutaneously (s.c.) administered centrally penetrating antagonists beta-funaltrexamine (mu), naltrindole (delta) and nor-binaltorphimine (kappa), and by the peripherally restricted antagonist naloxone methiodide (NLXM). NLXM was also injected intracerebroventricularly (i.c.v.) before i.p. loperamide. Mu-, kappa- and, to a lesser degree, delta-receptors were expressed on peripheral nerve terminals in the peritoneum. The anatomical distribution of the opioid receptor staining was very similar to the staining for calcitonin gene-related peptide, a marker of sensory neurons. Morphine, U50488 and, to a lesser degree, SNC80 blocked acetic and acid induced writhes. These effects were reversed by beta-funaltrexamine, nor-binaltorphimine and naltrindole, respectively. NLXM (s.c.) reversed antinociceptive effects of morphine, SNC80 and U50488 by 57%, 80% and 47%, respectively. Loperamide (0.05 mg/kg)-induced antinociception was reversed by s.c. beta-funaltrexamine and NLXM. Loperamide (0.1 mg/kg)-induced antinociception was completely blocked by s.c. beta-funaltrexamine but was only attenuated (by 50%) by s.c. or i.c.v. NLXM. In conclusion, systemically administered centrally penetrating mu-, delta- and kappa-agonists produced a substantial part of antinociception through peripheral opioid receptors. Higher dose loperamide-induced antinociception involved also central opioid receptors.
阿片类药物的作用是由中枢和外周阿片受体介导的。在此，我们研究了每种受体群体对全身给药的中枢穿透性阿片类药物以及洛哌丁胺（一种外周作用受限的阿片类药物）所引发的镇痛作用的相对贡献。通过腹腔注射0.6%乙酸诱导小鼠产生伤害感受（腹部扭体）。我们通过免疫组织化学分析了腹膜中阿片受体的表达，腹腔注射μ（吗啡、洛哌丁胺）、δ（SNC80）和κ（U50488）受体激动剂后的镇痛作用，以及皮下注射中枢穿透性拮抗剂β-氟奈曲胺（μ）、纳曲吲哚（δ）和去甲二氢吗啡酮（κ）以及外周作用受限的拮抗剂甲硫氨酸纳洛酮（NLXM）后的镇痛作用可逆性。在腹腔注射洛哌丁胺前，也将NLXM脑室内注射。μ、κ以及程度较轻的δ受体表达于腹膜中的外周神经末梢。阿片受体染色的解剖分布与降钙素基因相关肽（一种感觉神经元标志物）的染色非常相似。吗啡、U50488以及程度较轻的SNC80可阻断乙酸诱导的扭体反应。这些作用分别被β-氟奈曲胺、去甲二氢吗啡酮和纳曲吲哚逆转。皮下注射NLXM分别使吗啡、SNC80和U50488的镇痛作用逆转57%、80%和47%。皮下注射β-氟奈曲胺和NLXM可逆转洛哌丁胺（0.05mg/kg）诱导的镇痛作用。皮下注射β-氟奈曲胺可完全阻断洛哌丁胺（0.1mg/kg）诱导的镇痛作用，但皮下或脑室内注射NLXM仅使其减弱（50%）。总之，全身给药的中枢穿透性μ、δ和κ激动剂通过外周阿片受体产生了很大一部分镇痛作用。高剂量洛哌丁胺诱导的镇痛作用也涉及中枢阿片受体。
