Christensen Dennis, Kayser Valérie
Unité de Recherches de Physiopharmacologie du Système Nerveux, INSERM U-161, 2 rue d'Alésia, 75014 Paris, France.
Pain. 2000 Dec 1;88(3):231-238. doi: 10.1016/S0304-3959(00)00334-1.
The inability of opioids to control pain over time may be influenced by different factors such as drug tolerance, hyperalgesia due to repeated morphine administration or progression of the original disease. In addition, chronic pain may alter morphine tolerance development. This study examined whether chronic morphine exposure differently affects mechanical and thermal stimulus evoked pain-related behaviour in non-operated, nerve-injured and sham-operated rats. Further, we studied the effect of nerve injury and sham surgery on the development of tolerance to the analgesic effect of morphine. Vocalization thresholds to paw pressure and struggle latencies to hindpaw immersion into a 46 degrees C hot-water bath were determined in groups of non-operated rats, nerve-injured (chronic constriction of the sciatic nerve) and sham-operated rats. Immediately thereafter, pretreatment regimens with s.c. injections of either saline or morphine (10 mg/kg) were started. Injections were given twice daily on post-operative days 12-15, when the abnormal pain behaviour in nerve-injured rats is at a stable maximum. On day 16, the effect of an acute dose of i.v. morphine (1 mg/kg) was tested. On day 12 the baseline vocalization threshold and struggle latency were decreased in nerve-injured but not in non- and sham-operated rats. Morphine pretreatment further decreased the vocalization threshold in nerve-injured rats and induced threshold reductions in non- and sham-operated rats. In the thermal test, morphine pretreatment produced no change in baseline latencies in any of the groups. Following morphine pretreatment, acute i.v. morphine on day 16 remained effective against both mechanical and thermal stimuli in non-operated rats, but was strongly reduced in nerve-injured rats. Sham-operated rats displayed a tendency towards a reduced effect of i.v. morphine after morphine pretreatment in the mechanical but not in the thermal test. The results suggest that mechanical afferent systems may be more sensitive to hyperalgesia associated with repetitive morphine injections than thermal systems and that nerve injury facilitates the development of tolerance to morphine analgesia.
随着时间的推移，阿片类药物无法控制疼痛可能受到不同因素的影响，如药物耐受性、反复给予吗啡导致的痛觉过敏或原发病的进展。此外，慢性疼痛可能会改变吗啡耐受性的发展。本研究考察了慢性吗啡暴露对未手术、神经损伤和假手术大鼠机械性和热刺激诱发的疼痛相关行为是否有不同影响。此外，我们研究了神经损伤和假手术对吗啡镇痛耐受性发展的影响。测定了未手术大鼠、神经损伤（坐骨神经慢性结扎）大鼠和假手术大鼠组对爪部压力的发声阈值以及后爪浸入46℃热水浴中的挣扎潜伏期。此后立即开始皮下注射生理盐水或吗啡（10mg/kg）的预处理方案。在术后第12 - 15天每天注射两次，此时神经损伤大鼠的异常疼痛行为处于稳定的最大值。在第16天，测试静脉注射吗啡（1mg/kg）急性剂量的效果。在第12天，神经损伤大鼠的基线发声阈值和挣扎潜伏期降低，但未手术和假手术大鼠未出现这种情况。吗啡预处理进一步降低了神经损伤大鼠的发声阈值，并使未手术和假手术大鼠的阈值降低。在热测试中，吗啡预处理在任何组中均未使基线潜伏期发生变化。吗啡预处理后，第16天静脉注射急性吗啡对未手术大鼠的机械性和热刺激仍有效，但在神经损伤大鼠中作用大幅降低。在机械性测试而非热测试中，假手术大鼠在吗啡预处理后静脉注射吗啡的效果有降低的趋势。结果表明，与热系统相比，机械传入系统可能对与重复注射吗啡相关的痛觉过敏更敏感，并且神经损伤促进了对吗啡镇痛耐受性的发展。
