Harms Jonathan, Stone Audrey J, Kaufman Marc P
Heart and Vascular Institute, The Pennsylvania State College of Medicine , Hershey, Pennsylvania.
J Neurophysiol. 2018 Jun 1;119(6):2052-2058. doi: 10.1152/jn.00034.2018. Epub 2018 Feb 21.
Patients with peripheral artery disease show an exaggerated pressor response to mild exercise, an effect attributable to the exercise pressor reflex, whose afferent arm comprises the thinly myelinated group III and unmyelinated group IV afferents. Previously, we found that DAMGO, a µ-opioid agonist injected into the femoral artery, attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries, a preparation that simulates the blood flow patterns to muscle that is seen in patients with peripheral artery disease. Continuing this line of investigation, we recorded the responses of group III and IV afferents to static contraction before and after injecting DAMGO (1 µg) into the superficial epigastric artery in rats with patent femoral arteries and in rats with ligated femoral arteries. In rats with patent arteries, DAMGO did not change the responses to contraction of either group III ( n = 9; P = 0.83) or group IV ( n = 8; P = 0.34) afferents. In contrast, in rats with ligated femoral arteries, DAMGO injection (1 µg) significantly decreased the responses to contraction of both group III afferents ( n = 9, P < 0.01) and group IV afferents ( n = 9; P < 0.01). DAMGO did not significantly attenuate the responses of either group III or IV afferents to capsaicin in rats with either patent or ligated femoral arteries. These findings are in agreement with our previous studies that showed that peripheral DAMGO injection attenuated the exercise pressor reflex in rats with ligated femoral arteries but had only a modest effect on the exercise pressor reflex in rats with patent femoral arteries. NEW & NOTEWORTHY In an animal model of peripheral artery disease, we show that the µ-opioid agonist, DAMGO reduces the afferent response rate resulting from stimulated static contraction. These results suggest that peripherally active opioid agonists that do not cross the blood-brain barrier may be therapeutic for treatment of peripheral artery disease without the negative and addictive side effects associated with opioids in the central nervous system.
外周动脉疾病患者对轻度运动表现出过度的升压反应，这种效应归因于运动升压反射，其传入支包括薄髓鞘的III类和无髓鞘的IV类传入神经。此前，我们发现，注入股动脉的μ阿片受体激动剂DAMGO可减弱结扎股动脉大鼠的过度运动升压反射，该制备方法模拟了外周动脉疾病患者肌肉的血流模式。继续这一研究方向，我们记录了在向具有通畅股动脉的大鼠和结扎股动脉的大鼠的腹壁浅动脉注射DAMGO（1μg）前后，III类和IV类传入神经对静态收缩的反应。在具有通畅动脉的大鼠中，DAMGO对III类传入神经（n = 9；P = 0.83）或IV类传入神经（n = 8；P = 0.34）对收缩的反应均无影响。相比之下，在结扎股动脉的大鼠中，注射DAMGO（1μg）显著降低了III类传入神经（n = 9，P < 0.01）和IV类传入神经（n = 9；P < 0.01）对收缩的反应。在具有通畅或结扎股动脉的大鼠中，DAMGO对III类或IV类传入神经对辣椒素的反应均无显著减弱作用。这些发现与我们之前的研究一致，即外周注射DAMGO可减弱结扎股动脉大鼠的运动升压反射，但对具有通畅股动脉的大鼠的运动升压反射仅有适度影响。新发现与值得注意之处 在一种外周动脉疾病动物模型中，我们表明μ阿片受体激动剂DAMGO可降低由刺激静态收缩引起的传入反应率。这些结果表明，不穿过血脑屏障的外周活性阿片类激动剂可能对治疗外周动脉疾病具有治疗作用，而无中枢神经系统中阿片类药物相关的负面和成瘾性副作用。
