Effects of naloxone and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 and the protein kinase inhibitors H7 and H8 on acute morphine dependence and antinociceptive tolerance in mice.
Effects of naloxone and D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 and the protein kinase inhibitors H7 and H8 on acute morphine dependence and antinociceptive tolerance in mice.
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发表时间：
1996-04
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通讯作者：
E. Bilsky;R. N. Bernstein;Z. Wang;W. Sadee;F. Porreca
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作者：
E. Bilsky;R. N. Bernstein;Z. Wang;W. Sadee;F. Porreca
先前的研究测量阿片抑制SH-SY 5 Y细胞中的环磷酸腺苷支持的假设，即连续激动剂刺激导致μ阿片受体逐渐转化为敏化或组成性活性状态，称为μ *。转化为mu* 被激酶抑制剂H7阻止，但不是其类似物H8。纳洛酮被认为是一种阻断mu* 活性的负性拮抗剂（反向激动剂），而D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2（CTAP）似乎是一种对mu* 活性没有影响的中性拮抗剂。最初的体内结果表明，mu* 活性可能在麻醉剂耐受性和依赖性中起作用（Wang等人，Life Sci. 54：PL339-PL350 1994）。本研究探讨了H7和H8、纳洛酮和CTAP在小鼠皮下注射诱导急性耐受和依赖后的药理作用。吗啡剂量（100 mg/kg）。身体依赖性定义为吗啡给药后4小时（最大身体依赖性时间）腹腔注射纳洛酮诱导的戒断跳跃。H7和H8（50 nmol或更少）均不诱导跳跃，影响吗啡抗伤害感受或产生显著的行为效应，当通过侧脑室（i. c. v.）或鞘内（i.th.）航线当在纳洛酮激发前30分钟给药时，H7，而不是H8，通过i. c. v.注射显著降低纳洛酮跳跃。将纳洛酮给予中枢神经系统，而不是通过i. p.给药，需要通过i. c. v.和i.th.联合注射。诱导完全戒断跳跃的途径（每个部位30 nmol）。相反，假定的中性拮抗剂CTAP在i. c. v.和i.th.共同注射时几乎不引起戒断跳跃，如所预期的，如果MU* 活性的调节在依赖性中起作用。然而，CTAP能够部分逆转纳洛酮（i. p.）当给予i. c. v.或i.th.时诱导跳跃，表明CTAP在μ * 上与纳洛酮竞争。此外，这些结果表明，脊髓和脊髓上的网站所需的充分阿片类药物戒断跳跃小鼠。还通过在55 ℃温水甩尾试验中测定对吗啡的反应来评价抗伤害耐受性。吗啡预处理（100 mg/kg，s.c.，-5小时）产生抗伤害耐受，如计算的吗啡A50值增加2.7倍所示。耐受性被H7逆转，但不是H8，处理（50 nmol，i. c. v.，约30分钟）。这些结果与致敏或组成性活性mu* 状态在麻醉耐受性和依赖性中起作用的假设一致。
Previous studies measuring opioid inhibition of cyclic adenosine monophosphate in SH-SY5Y cells supported the hypothesis that continuous agonist stimulation causes a gradual conversion of the mu opioid receptor to a sensitized or constitutively active state termed mu*. Conversion to mu* was prevented by the kinase inhibitor H7, but not its close analog H8. Naloxone was proposed to act as a negative antagonist (inverse agonist) blocking mu* activity, whereas D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) appeared to act as a neutral antagonist having no effect on mu* activity. Initial in vivo results indicated that mu* activity may play a role in narcotic tolerance and dependence (Wang et al., Life Sci. 54: PL339-PL350 1994). Our study explores the pharmacology of H7 and H8, naloxone and CTAP in mice after induction of acute tolerance and dependence induced by a single s.c. dose of morphine (100 mg/kg). Physical dependence was defined by withdrawal jumping induced by i.p. naloxone injections 4 hr after the morphine dose, the time of maximal physical dependence. Neither H7 nor H8 (50 nmol or less) induced jumping, affected morphine antinociception or produced significant behavioral effects, when injected by the intracerebroventricular (i.c.v.) or intrathecal (i.th.) routes. When given 30 min before the naloxone challenge, H7, but not H8, significantly reduced naloxone jumping by i.c.v. injection. Administration of naloxone into the central nervous system, rather than by i.p. administration, required coinjection by both i.c.v. and i.th. routes to elicit full withdrawal jumping (30 nmol at each site). In contrast, the putative neutral antagonist CTAP caused little withdrawal jumping when coinjected i.c.v. and i.th., as expected if modulation of mu* activity played a role in dependence. However, CTAP was capable of partially reversing naloxone (i.p.) induced jumping when given either i.c.v. or i.th., indicating that CTAP competes with naloxone at mu*. Moreover, these results demonstrate that both spinal and supraspinal sites are required for full opioid withdrawal jumping in mice. Antinociceptive tolerance was also evaluated by determining the response to morphine in the 55 degrees C warm-water tail-flick test. Morphine pretreatment (100 mg/kg, s.c., -5 hr) produced antinociceptive tolerance as shown by a 2.7-fold increase in the calculated morphine A50 value. Tolerance was reversed by H7, but not H8, treatment (50 nmol, i.c.v., -30 min). These results are consistent with the hypothesis that a sensitized or constitutively active mu* state plays a role in narcotic tolerance and dependence.