Chen Shao-Rui, Pan Hui-Lin
Department of Anesthesiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
J Neurophysiol. 2006 May;95(5):3086-96. doi: 10.1152/jn.01343.2005. Epub 2006 Feb 8.
Systemic administration of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, removes transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons and impairs thermal but not mechanical nociception in adult animals. In this study, we determined how loss of TRPV1-expressing sensory neurons alters the antinociceptive effect of mu opioids and mu opioid receptors in the spinal cord. The effect of morphine and (D-Ala2,N-Me-Phe4,Gly-ol5)-enkephalin (DAMGO) was measured by testing the paw mechanical withdrawal threshold in rats treated with RTX or vehicle. RTX treatment deleted TRPV1-immunoreactive dorsal root ganglion neurons and nerve terminals in the spinal dorsal horn. Also the mu opioid receptor immunoreactivity was markedly reduced in the superficial dorsal horn of RTX-treated rats. However, RTX treatment did not affect the dorsal horn neurons labeled with both TRPV1- and mu opioid receptor-immunoreactivity. Surprisingly, intrathecal morphine or DAMGO produced a greater increase in the withdrawal threshold in RTX- than in vehicle-treated rats. The duration of the effect of intrathecal morphine and DAMGO in RTX-treated rats was also profoundly increased. Furthermore, the antinociceptive effect of systemic morphine was significantly potentiated in RTX-treated rats. The B(MAX) (but not K(D)) of [3H]-DAMGO binding and DAMGO-stimulated [35S]GTPgammaS activity in the dorsal spinal cord were significantly reduced in the RTX group. This study provides novel information that loss of TRPV1 afferent neurons eliminates presynaptic mu opioid receptors present on TRPV1-expressing afferent neurons but paradoxically potentiates the analgesic effect of mu opioid agonists. Mechano-nociception, transmitted through non-TRPV1 sensory neurons, is subject to potent modulation by mu opioid agonists.
树脂毒素（RTX）是一种超强力辣椒素类似物，全身给药可消除表达瞬时受体电位香草酸亚型1（TRPV1）的传入神经元，并损害成年动物的热痛觉但不影响机械性伤害感受。在本研究中，我们确定了表达TRPV1的感觉神经元缺失如何改变脊髓中μ阿片类药物和μ阿片受体的镇痛作用。通过测试用RTX或赋形剂处理的大鼠的爪机械退缩阈值来测量吗啡和（D-丙氨酸2，N-甲基苯丙氨酸4，甘氨醇5）-脑啡肽（DAMGO）的作用。RTX处理消除了脊髓背角中TRPV1免疫反应性背根神经节神经元和神经末梢。此外，RTX处理的大鼠背角浅层中μ阿片受体免疫反应性明显降低。然而，RTX处理并不影响同时标记有TRPV1和μ阿片受体免疫反应性的背角神经元。令人惊讶的是，鞘内注射吗啡或DAMGO在RTX处理的大鼠中比在赋形剂处理的大鼠中产生更大的退缩阈值升高。鞘内注射吗啡和DAMGO在RTX处理的大鼠中的作用持续时间也显著延长。此外，全身注射吗啡在RTX处理的大鼠中的镇痛作用明显增强。RTX组脊髓背角中[3H]-DAMGO结合的B（MAX）（而非K（D））和DAMGO刺激的[35S]GTPγS活性显著降低。本研究提供了新的信息，即TRPV1传入神经元的缺失消除了表达TRPV1的传入神经元上存在的突触前μ阿片受体，但矛盾的是增强了μ阿片激动剂的镇痛作用。通过非TRPV1感觉神经元传递的机械性伤害感受受到μ阿片激动剂的强力调节。
