μ-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain
μ-opioid receptor activation modulates transient receptor potential vanilloid 1 (TRPV1) currents in sensory neurons in a model of inflammatory pain
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DOI：
10.1124/mol.106.026740
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Zoellner, Christian
中科院分区：
文献类型：
--
作者：
Endres-Becker, Jeannette;Heppenstall, Paul A.;Zoellner, Christian
目前炎性疼痛的治疗包括阿片受体激动剂的外周应用。阿片受体的激活调节电压门控离子通道，但尚不清楚阿片类药物是否也可以影响配体门控离子通道[例如，瞬时受体电位香草酸1型（TRPV 1）]。TRPV 1通道参与与组织炎症相关的热超敏反应的发展。在这项研究中，我们研究了μ阿片受体和TRPV 1的表达在初级传入神经元的背根神经节（DRG）在完全弗氏佐剂（CFA）诱导的爪子炎症。此外，本研究检查了DRG神经元中TRPV 1的活性是否可以被μ阿片受体（μ受体）配体抑制，以及这种抑制在CFA炎症后是否增加。免疫组化显示TRPV 1和mu受体在DRG神经元中共定位。CFA诱导的炎症显著增加TRPV 1和μ受体阳性DRG神经元的数量，以及TRPV 1结合位点。在全细胞膜片钳研究中，阿片类药物以纳洛酮和百日咳毒素敏感的方式显著降低辣椒素诱导的TRPV 1电流。吗啡对TRPV 1的抑制作用可被forskolin和8-bromo-cAMP阻断。在炎症过程中，TRPV 1的增加显然与μ受体的增加相抗衡。然而，在单个分离的DRG神经元中，吗啡的抑制作用在有和没有CFA炎症的动物之间没有差异。在体内实验中，我们发现，局部应用吗啡减少辣椒素引起的热异常性疼痛。总之，我们的研究结果表明，μ受体激活可以通过G（i/o）蛋白和cAMP途径抑制TRPV 1的活性。这些观察结果证明了外周作用μ受体配体在炎性疼痛中镇痛功效的重要新机制。
Current therapy for inflammatory pain includes the peripheral application of opioid receptor agonists. Activation of opioid receptors modulates voltage-gated ion channels, but it is unclear whether opioids can also influence ligand-gated ion channels [e.g., the transient receptor potential vanilloid type 1 (TRPV1)]. TRPV1 channels are involved in the development of thermal hypersensitivity associated with tissue inflammation. In this study, we investigated mu-opioid receptor and TRPV1 expression in primary afferent neurons in the dorsal root ganglion (DRG) in complete Freund's adjuvant (CFA)-induced paw inflammation. In addition, the present study examined whether the activity of TRPV1 in DRG neurons can be inhibited by mu-opioid receptor (mu-receptor) ligands and whether this inhibition is increased after CFA inflammation. Immunohistochemistry demonstrated colocalization of TRPV1 and mu-receptors in DRG neurons. CFA-induced inflammation increased significantly the number of TRPV1- and mu-receptor-positive DRG neurons, as well as TRPV1 binding sites. In whole-cell patch clamp studies, opioids significantly decreased capsaicin-induced TRPV1 currents in a naloxone-and pertussis toxin-sensitive manner. The inhibitory effect of morphine on TRPV1 was abolished by forskolin and 8-bromo-cAMP. During inflammation, an increase in TRPV1 is apparently rivaled by an increase of mu-receptors. However, in single dissociated DRG neurons, the inhibitory effects of morphine are not different between animals with and without CFA inflammation. In in vivo experiments, we found that locally applied morphine reduced capsaicin-induced thermal allodynia. In summary, our results indicate that mu-receptor activation can inhibit the activity of TRPV1 via G(i/o) proteins and the cAMP pathway. These observations demonstrate an important new mechanism underlying the analgesic efficacy of peripherally acting mu-receptor ligands in inflammatory pain.