It was recently shown that local injection, systemic administration or topical application of the peripherally-restricted mu-opioid receptor (MOR) agonist loperamide (Lo) and the delta-opioid receptor (DOR) agonist oxymorphindole (OMI) synergized to produce highly potent anti-hyperalgesia that was dependent on both MOR and DOR located in the periphery. We assessed peripheral mechanisms by which this Lo/OMI combination produces analgesia in mice expressing the light-sensitive protein channelrhodopsin2 (ChR2) in neurons that express Na_V1.8 voltage-gated sodium channels. These mice (Na_V1.8-ChR2⁺) enabled us to selectively target and record electrophysiological activity from these neurons (the majority of which are nociceptive) using blue light stimulation of the hind paw. We assessed the effect of Lo/OMI on nociceptor activity in both naïve mice and mice treated with complete Freund’s adjuvant (CFA) to induce chronic inflammation of the hind paw. Teased fiber recording of tibial nerve fibers innervating the plantar hind paw revealed that the Lo/OMI combination reduced responses to light stimulation in naïve mice and attenuated spontaneous activity (SA) as well as responses to light and mechanical stimuli in CFA-treated mice. These results show that Lo/OMI reduces activity of C-fiber nociceptors that express Na_V1.8 and corroborate recent behavioral studies demonstrating the potent analgesic effects of this drug combination. Because of its peripheral site of action, Lo/OMI might produce effective analgesia without the side effects associated with activation of opioid receptors in the central nervous system.

最近表明，局部注射、全身给药或局部应用外周限制性 μ-阿片受体 (MOR) 激动剂洛哌丁胺 (Lo) 和 δ-阿片受体 (DOR) 激动剂羟吗啉 (OMI) 可协同产生高效抗- 依赖于位于外周的 MOR 和 DOR 的痛觉过敏。我们评估了这种 Lo/OMI 组合在表达 Na _V 1.8 电压门控钠通道的神经元中表达光敏蛋白通道视紫红质 2 (ChR2) 的小鼠中产生镇痛的外周机制。这些小鼠 ( Na _V 1.8-ChR2 ⁺) 使我们能够使用后爪的蓝光刺激选择性地靶向和记录这些神经元（其中大多数是伤害性的）的电生理活动。我们评估了 Lo/OMI 对幼稚小鼠和用完全弗氏佐剂 (CFA) 治疗以诱导后爪慢性炎症的小鼠的伤害感受器活性的影响。支配足底后爪的胫神经纤维的梳理纤维记录显示，Lo/OMI 组合减少了幼稚小鼠对光刺激的反应，并减弱了自发活动 (SA) 以及 CFA 治疗小鼠对光和机械刺激的反应。这些结果表明 Lo/OMI 降低了表达 Na _V的 C 纤维伤害性感受器的活性1.8 并证实最近的行为研究证明了这种药物组合的有效镇痛作用。由于其作用于外周部位，Lo/OMI 可能会产生有效的镇痛作用，而不会产生与中枢神经系统中阿片受体激活相关的副作用。