Valverde O, Fournié-Zaluski M C, Roques B P, Maldonado R
Département de Pharmacochimie Moléculaire et Structurale U266 INSERM, URA D 1500 URF des Sciences Pharmaceutiques et Biologiques, Faculté de Pharmacie, Université René Descartes, Paris, France.
Eur J Pharmacol. 1996 Sep 19;312(1):15-25. doi: 10.1016/0014-2999(96)00437-2.
The complete inhibitor of the enkephalin degrading enzymes, RB 101, N-{(R,S)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithio]-1- oxopropyl}-L-phenylalanine benzyl ester, which crosses the blood-brain barrier, induced antinociceptive effects similar to those of exogenous opiates. The almost complete absence of tolerance and dependence after chronic administration of RB 101 is therefore due to limited stimulation of opioid receptors by 'protected' endogenous enkephalins. In order to clarify the mechanisms involved in these response, we have investigated the participation of several brain structures in the antinociceptive effects induced by systemic administration of morphine or RB 101. Rats were implanted with bilateral cannulae into the ventro-basal thalamus, central amygdala and periaqueductal gray matter, or with a cannula into the raphe magnus nucleus. The antinociceptive responses induced by systemic morphine or RB 101 were measured by using the tail-electrical stimulation test, where three different thresholds were determined: motor response, vocalization and vocalization post-discharge. The ability of the opioid receptor antagonist methylnaloxonium to block these antinociceptive responses was evaluated after local injection into the different brain structures. The blockade of morphine- and RB 101-induced antinociception was similar, and was stronger when methylnaloxonium was injected into the periaqueductal gray matter and raphe magnus nucleus than when it was injected into the ventro-basal thalamus and amygdala. These results suggest that brain structures related to the control of pain seem to be the same for the antinociception induced by exogenous opiates and endogenous opioids.
脑啡肽降解酶的完全抑制剂RB 101，即N-{（R，S）-2-苄基-3[（S）-（2-氨基-4-甲硫基）丁基二硫代]-1-氧代丙基}-L-苯丙氨酸苄酯，可穿过血脑屏障，诱导出与外源性阿片类药物相似的抗伤害感受作用。因此，长期给予RB 101后几乎完全不存在耐受性和依赖性，这是由于“受保护的”内源性脑啡肽对阿片受体的刺激有限。为了阐明这些反应所涉及的机制，我们研究了几个脑结构在全身给予吗啡或RB 101所诱导的抗伤害感受作用中的参与情况。给大鼠双侧植入套管至腹侧基底丘脑、中央杏仁核和导水管周围灰质，或植入一个套管至中缝大核。通过尾部电刺激试验测量全身给予吗啡或RB 101所诱导的抗伤害感受反应，确定三个不同的阈值：运动反应、发声和发声后放电。在向不同脑结构局部注射后，评估阿片受体拮抗剂甲基纳洛酮阻断这些抗伤害感受反应的能力。吗啡和RB 101诱导的抗伤害感受的阻断情况相似，当甲基纳洛酮注射到导水管周围灰质和中缝大核时比注射到腹侧基底丘脑和杏仁核时更强。这些结果表明，与疼痛控制相关的脑结构在外源性阿片类药物和内源性阿片类物质诱导的抗伤害感受方面似乎是相同的。
