Ossipov M H, Lopez Y, Nichols M L, Bian D, Porreca F
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724, USA.
Neurosci Lett. 1995 Oct 20;199(2):83-6. doi: 10.1016/0304-3940(95)12026-z.
Nerve ligation injury in rats produces increased sensitivity and exaggerated responses to nociceptive stimuli (hyperalgesia) as well as nociceptive responses to normally innocuous stimuli (allodynia) analogous to clinical conditions of neuropathic pain. However, the effect of nerve injury on acute nociception has not been extensively studied. Nerve ligation injury was produced by unilateral ligation of the L5 and L6 spinal roots of the sciatic nerve of male Sprague-Dawley rats. Intrathecal (i.th.) catheters were inserted for spinal drug administration. Response to acute nociception was measured by determining the latency to a rapid flick of the tail (TF) after immersion into a 55 degrees C water bath before (control) and after i.th. morphine administration. No change in baseline response to the nociceptive stimulus was observed in either sham-operated or nerve-injured rats. In sham-operated rats, morphine produced dose-dependent antinociception with a 97 +/- 2.3% maximal possible effect (MPE) at a 60 microgram dose; in these controls A50 (95% CL) was 22 micrograms (17-30 micrograms). Morphine administered to rats with nerve injury also produced dose-dependent increase in TF latency, but an MPE of only 60 +/- 17% was obtained at 100 micrograms; higher doses elicited signs of behavioral toxicity. While it was not possible to produce a proper dose-response curve with i.th. morphine in animals with nerve injury, an estimation of the A50 showed approximately a four-fold loss of potency compared to sham-operated controls. Antinociception was readily reversed by naloxone (5 mg/kg, i.p.) in both groups. These data indicate that nerve ligation injury reduces the potency and efficacy of i.th. morphine. While the reasons for this loss of morphine activity in nerve injured animals are unknown, it is possible to speculate that (a) degeneration of primary afferents subsequent to nerve ligation injury might result in a loss of presynaptic opioid (mu?) receptors in the dorsal horn, thereby reducing the antinociceptive activity of morphine at the spinal level; (b) changes in the efficiency of post-receptor transduction may occur following nerve injury which can reduce opioid efficacy; (c) changes in levels of spinal neurotransmitters (e.g., cholecystokinin) may act to diminish opioid action; or (d) sustained afferent input from the site of the injury may be important in limiting the activity of opioids.
大鼠的神经结扎损伤会导致对伤害性刺激的敏感性增加和反应过度（痛觉过敏），以及对通常无害刺激产生伤害性反应（异常性疼痛），这类似于神经性疼痛的临床症状。然而，神经损伤对急性痛觉的影响尚未得到广泛研究。通过单侧结扎雄性Sprague-Dawley大鼠坐骨神经的L5和L6脊神经根来造成神经结扎损伤。插入鞘内（i.th.）导管用于脊髓给药。通过测定在鞘内注射吗啡之前（对照）和之后将尾巴浸入55摄氏度水浴中后快速甩尾（TF）的潜伏期来测量对急性痛觉的反应。在假手术组或神经损伤组大鼠中，均未观察到对伤害性刺激的基线反应有变化。在假手术组大鼠中，吗啡产生剂量依赖性的镇痛作用，在60微克剂量时最大可能效应（MPE）为97±2.3%；在这些对照组中，半数有效量（A50，95%可信区间）为22微克（17 - 30微克）。给神经损伤的大鼠注射吗啡也会使TF潜伏期产生剂量依赖性增加，但在100微克时仅获得60±17%的MPE；更高剂量会引发行为毒性迹象。虽然在神经损伤的动物中无法用鞘内注射吗啡得出合适的剂量 - 反应曲线，但对A50的估计显示，与假手术对照组相比，效力大约损失了四倍。两组中，纳洛酮（5毫克/千克，腹腔注射）均可使镇痛作用迅速逆转。这些数据表明，神经结扎损伤会降低鞘内注射吗啡的效力和效果。虽然神经损伤动物中吗啡活性丧失的原因尚不清楚，但有可能推测：（a）神经结扎损伤后初级传入神经的退化可能导致背角中突触前阿片样物质（μ？）受体的丧失，从而降低吗啡在脊髓水平的镇痛活性；（b）神经损伤后受体后转导效率可能发生变化，这会降低阿片样物质的效力；（c）脊髓神经递质（如胆囊收缩素）水平的变化可能会减弱阿片样物质的作用；或者（d）来自损伤部位的持续传入输入可能对限制阿片样物质的活性很重要。
