From the Department of Anesthesiology and Critical Care Medicine (Vinod T., M.A., F.Y., Vineeta T., S.-Q.H., T.Z., B.S., S.A.G., Z.C., S.N.R., Y.G.) the Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology (M.A., Q.Z., X.D.) Department of Pharmacology and Molecular Sciences and the Center for Epigenetics (K.E.S.) the Howard Hughes Medical Institute (X.D.), Johns Hopkins University School of Medicine, Baltimore, Maryland Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India (Vinod T.) Department of Neurology, Tiantan Hospital, Capital Medical University, Beijing, China (T.Z.) Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Wuhan, China (B.S.) the Department of Orthopedics, Luhe Hospital, Capital Medical University, Beijing, China (X.C.).
Anesthesiology. 2018 Jun;128(6):1220-1236. doi: 10.1097/ALN.0000000000002191.
Ongoing neuropathic pain is difficult to treat. The authors examined whether dermorphin [D-Arg2, Lys4] (1-4) amide, a peripherally acting µ-opioid receptor agonist, attenuates ongoing pain-associated manifestations after nerve injury in rats and mice.
Using conditioned place preference assay, the authors tested whether animals show a preference to the environment associated with drug treatment. Wide-dynamic range and dorsal root ganglion neuronal activities were measured by electrophysiology recording and calcium imaging.
Nerve-injured animals stayed longer in dermorphin [D-Arg2, Lys4] (1-4) amide-paired chamber after conditioning than during preconditioning (rats: 402.4 ± 61.3 vs. 322.1 ± 45.0 s, 10 mg/kg, n = 9, P = 0.009; mice: 437.8 ± 59.4 vs. 351.3 ± 95.9 s, 2 mg/kg, n = 8, P = 0.047). Topical ganglionic application of dermorphin [D-Arg2, Lys4] (1-4) amide (5 μM, 1 μl, n = 5) reduced the numbers of small-diameter dorsal root ganglion neurons that showed spontaneous activity (1.1 ± 0.4 vs. 1.5 ± 0.3, P = 0.044) and that were activated by test stimulation (15.5 ± 5.5 vs. 28.2 ± 8.2, P = 0.009) after injury. In neuropathic rats, dermorphin [D-Arg2, Lys4] (1-4) amide (10 mg/kg, n = 8) decreased spontaneous firing rates in wide-dynamic range neurons to 53.2 ± 46.6% of predrug level, and methylnaltrexone (5 mg/kg, n = 9) blocked dermorphin [D-Arg2, Lys4] (1-4) amide-induced place preference and inhibition of wide-dynamic range neurons. Dermorphin [D-Arg2, Lys4] (1-4) amide increased paw withdrawal threshold (17.5 ± 2.2 g) from baseline (3.5 ± 0.7 g, 10 mg/kg, n = 8, P = 0.002) in nerve-injured rats, but the effect diminished after repeated administrations.
Peripherally acting μ-opioids may attenuate ongoing pain-related behavior and its neurophysiologic correlates. Yet, repeated administrations cause antiallodynic tolerance.
持续性神经病理性疼痛难以治疗。作者研究了在外周作用的 μ 阿片受体激动剂 Dermorphin [D-Arg2, Lys4] (1-4)酰胺是否能减轻神经损伤后大鼠和小鼠的持续性疼痛相关表现。
作者使用条件性位置偏好试验来测试动物是否对与药物治疗相关的环境表现出偏好。通过电生理学记录和钙成像测量宽动态范围和背根神经节神经元活动。
与预处理相比，神经损伤动物在 Dermorphin [D-Arg2, Lys4] (1-4)酰胺配对室中停留的时间更长（大鼠：402.4 ± 61.3 秒与 322.1 ± 45.0 秒，10mg/kg，n = 9，P = 0.009；小鼠：437.8 ± 59.4 秒与 351.3 ± 95.9 秒，2mg/kg，n = 8，P = 0.047）。局部应用 Dermorphin [D-Arg2, Lys4] (1-4)酰胺（5 μM，1 μl，n = 5）可减少小直径背根神经节神经元的自发活动（1.1 ± 0.4 与 1.5 ± 0.3，P = 0.044）和对测试刺激的激活（15.5 ± 5.5 与 28.2 ± 8.2，P = 0.009）。在神经病理性大鼠中，Dermorphin [D-Arg2, Lys4] (1-4)酰胺（10mg/kg，n = 8）将宽动态范围神经元的自发放电率降低至药物前水平的 53.2 ± 46.6%，甲基纳曲酮（5mg/kg，n = 9）阻断了 Dermorphin [D-Arg2, Lys4] (1-4)酰胺诱导的位置偏好和宽动态范围神经元的抑制。Dermorphin [D-Arg2, Lys4] (1-4)酰胺增加了神经损伤大鼠的足底撤回阈值（17.5 ± 2.2g）（基线为 3.5 ± 0.7g，10mg/kg，n = 8，P = 0.002），但在重复给药后，这种作用减弱。
外周作用的 μ 阿片类药物可能会减轻持续性疼痛相关行为及其神经生理相关性。然而，重复给药会导致抗痛觉过敏耐受。
