Laferrière Andrè, Colin-Durand Jessica, Moss Immanuela Ravè
Developmental Respiratory Laboratory, Montreal Children's Hospital Research Institute, Montreal, QC, Canada H3H 1P3.
Brain Res Dev Brain Res. 2005 May 12;156(2):210-7. doi: 10.1016/j.devbrainres.2005.03.002.
Whereas developmental changes in analgesic sensitivity and tolerance to the mu-opioid agonist fentanyl have been reported, knowledge of respiratory responses to that drug is lacking. Using 7- and 14-day-old (P7, P14) and adult conscious rats, we first established, using whole body plethysmography, the fentanyl dose that decreased minute ventilation by 50% (ED50) at each age. ED50 increased with postnatal age (40, 60 and 120 microg/kg sc, respectively), indicating a high sensitivity to fentanyl in the youngest rats that decreased with maturation. In separate rat groups of the 3 ages, we injected each ED50 dose, once a day, for several consecutive days, until tolerance was established. Tolerance was defined as a reduction in respiratory depression from 50% to 75% of baseline. All age groups reached tolerance in minute ventilation, respiratory frequency, tidal volume and instantaneous flow (equivalent to respiratory drive). The P14 rat pups attained tolerance more rapidly (at 2.6 days) than did either the younger (5.1 days) or the adult rats (4.4 days). These results indicate that respiratory sensitivity and tolerance to fentanyl in rat vary in a distinct manner during maturation.
虽然已有报道称阿片类镇痛药敏感性及对μ-阿片受体激动剂芬太尼的耐受性存在发育变化，但对该药物呼吸反应的了解却很匮乏。我们使用7日龄、14日龄（P7、P14）及成年清醒大鼠，首先通过全身体积描记法确定了每个年龄段使分钟通气量降低50%（ED50）的芬太尼剂量。ED50随出生后年龄增加（分别为40、60和120微克/千克皮下注射），表明最年幼的大鼠对芬太尼高度敏感，且这种敏感性随成熟而降低。在3个年龄组的不同大鼠群体中，我们连续数天每天注射一次各ED50剂量，直至建立耐受性。耐受性定义为呼吸抑制从基线水平降低50%至75%。所有年龄组在分钟通气量、呼吸频率、潮气量和瞬时流量（等同于呼吸驱动）方面均达到耐受性。P14幼鼠比年幼大鼠（5.1天）或成年大鼠（4.4天）更快（2.6天）达到耐受性。这些结果表明，大鼠对芬太尼的呼吸敏感性和耐受性在成熟过程中以独特方式变化。
