Bertman L J, Advokat C
Department of Psychology, Louisiana State University, Baton Rouge 70803, USA.
Brain Res. 1995 Jun 26;684(1):8-18. doi: 10.1016/0006-8993(95)00321-g.
Baclofen is particularly effective in treating spasticity of spinal origin in humans. However, most investigations of this drug in animals have only assessed its antinociceptive effect, presumably because of the difficulty in developing animal models of spasticity. This study attempted to evaluate both, the antinociceptive and antispastic action of (-)-baclofen (the more active enantiomer) by incorporating the chronic spinal preparation, in which spasticity gradually develops following spinal transection. Separate groups of intact, acute (1 day) or chronic (20-25 days) spinal rats were pretested on the nociceptive tail-flick (TF) assay prior to either subcutaneous (SC; 1-30 mg/kg) or intrathecal (IT; 0.1-12 micrograms) injection of (-)-baclofen and retested at specific post-injection intervals. Hindlimb spasticity was elicited in chronic spinal rats by mechanical stimulation to the abdomen. Because the clinical use of baclofen generally involves chronic administration, both responses were tested for 3 successive days to assess tolerance. Results confirmed the analgesic effect of SC and IT (-)-baclofen in intact rats. As previously reported, the antinociceptive effect of IT (-)-baclofen was increased in acute spinal rats. However, three weeks after spinalization there was a profound decrease in this response. In contrast, antinociception produced by SC (-)-baclofen was reduced in acute and chronic spinal rats compared to intact animals; but there was no difference between the acute and chronic conditions. In spite of this differential decrease in antinociception after IT, relative to SC, administration, both routes of administration produced an antispastic effect in chronic spinal rats. There was no antinociceptive tolerance to SC administration and only minimal tolerance to IT (-)-baclofen (in intact rats); the antispastic effect did not become tolerant. A peripheral action might explain the dichotomy between SC and IT (-)-baclofen in regard to antinociception. However, further research is needed to determine why both routes of administration were effective against spasticity while only SC (-)-baclofen retained an antinociceptive action in chronic spinal rats.
巴氯芬在治疗人类脊髓源性痉挛方面特别有效。然而，大多数在动物身上对这种药物的研究仅评估了其抗伤害感受作用，大概是因为难以建立痉挛的动物模型。本研究试图通过采用慢性脊髓制备方法来评估（-）-巴氯芬（活性更强的对映体）的抗伤害感受和抗痉挛作用，在该制备方法中，脊髓横断后痉挛会逐渐发展。在皮下（SC；1 - 30毫克/千克）或鞘内（IT；0.1 - 12微克）注射（-）-巴氯芬之前，分别对完整、急性（1天）或慢性（20 - 25天）脊髓大鼠组进行伤害性甩尾（TF）试验预测试，并在注射后的特定时间间隔进行重新测试。通过对慢性脊髓大鼠腹部进行机械刺激来诱发后肢痉挛。由于巴氯芬的临床使用通常涉及长期给药，两种反应均连续测试3天以评估耐受性。结果证实了SC和IT（-）-巴氯芬在完整大鼠中的镇痛作用。如先前报道，IT（-）-巴氯芬在急性脊髓大鼠中的抗伤害感受作用增强。然而，脊髓横断三周后，这种反应大幅下降。相比之下，与完整动物相比，SC（-）-巴氯芬在急性和慢性脊髓大鼠中产生的抗伤害感受作用降低；但急性和慢性情况之间没有差异。尽管IT给药后抗伤害感受有这种差异降低，相对于SC给药而言，两种给药途径在慢性脊髓大鼠中均产生了抗痉挛作用。对SC给药没有抗伤害感受耐受性，对IT（-）-巴氯芬（在完整大鼠中）只有最小的耐受性；抗痉挛作用没有产生耐受性。外周作用可能解释了SC和IT（-）-巴氯芬在抗伤害感受方面的二分法。然而，需要进一步研究来确定为什么两种给药途径对痉挛都有效，而只有SC（-）-巴氯芬在慢性脊髓大鼠中保留了抗伤害感受作用。
