Walker S M, Fitzgerald M
Portex Anaesthesia Unit, UCL Institute of Child Health, University College London, London, UK.
Br J Pharmacol. 2007 Aug;151(8):1334-42. doi: 10.1038/sj.bjp.0707290. Epub 2007 May 29.
The selective alpha(2)-adrenergic agonist dexmedetomidine is used clinically for analgesia and sedation, but effects in early life are not well characterized. Investigation of age-related effects of dexmedetomidine is important for evaluating responses to exogenously administered analgesics and provides insight into postnatal function of noradrenergic pathways.
We examined effects of epidural dexmedetomidine in anaesthetized rat pups (3, 10 and 21 postnatal days) using a quantitative model of nociception and C-fibre induced hyperalgesia. Electromyographic recordings of withdrawal responses to hindpaw mechanical stimuli measured effects of dexmedetomidine upon the baseline reflex and the response to mustard oil application on the hindpaw (primary hyperalgesia) or hindlimb (secondary hyperalgesia). In addition, we compared epidural with systemic administration, examined effects of spinal transection and evaluated heart rate changes following dexmedetomidine.
Epidural dexmedetomidine dose-dependently prevented mustard oil-induced hyperalgesia at all ages but dose requirements were lower in the youngest pups. Higher doses also suppressed the baseline nociceptive reflex when given epidurally, but had no effect when given systemically. Analgesic efficacy was the same for primary and secondary hyperalgesia, and was not diminished by spinal cord transection.
Our laboratory studies predict that spinally mediated alpha(2)-agonist analgesia would be effective throughout postnatal development, dose requirements would be lower in early life and selective anti-hyperalgesic effects could be achieved with epidural administration at doses lower than associated with antinociceptive or cardiovascular effects. Clinical trials of alpha(2) agonists in neonates and infants should consider developmentally regulated changes.
选择性α₂肾上腺素能激动剂右美托咪定在临床上用于镇痛和镇静，但对早期生命阶段的影响尚未完全明确。研究右美托咪定与年龄相关的效应对于评估对外源性镇痛药的反应很重要，并且有助于深入了解去甲肾上腺素能通路的产后功能。
我们使用伤害感受定量模型和C纤维诱导的痛觉过敏，研究了硬膜外给予右美托咪定对麻醉的新生大鼠（出生后3、10和21天）的影响。通过对后爪机械刺激的撤腿反应进行肌电图记录，来测定右美托咪定对基线反射以及后爪（原发性痛觉过敏）或后肢（继发性痛觉过敏）涂抹芥子油后的反应的影响。此外，我们比较了硬膜外给药与全身给药的效果，研究了脊髓横断的影响，并评估了右美托咪定给药后的心率变化。
硬膜外给予右美托咪定在所有年龄段均能剂量依赖性地预防芥子油诱导的痛觉过敏，但最年幼的幼崽所需剂量较低。硬膜外给予较高剂量时也会抑制基线伤害性反射，但全身给药时则无此作用。原发性和继发性痛觉过敏的镇痛效果相同，且脊髓横断不会减弱这种效果。
我们的实验室研究预测，脊髓介导的α₂激动剂镇痛在整个产后发育过程中均有效，早期生命阶段所需剂量较低，并且硬膜外给药以低于抗伤害感受或心血管效应相关剂量即可实现选择性抗痛觉过敏作用。在新生儿和婴儿中进行α₂激动剂的临床试验时应考虑发育调节变化。
