Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene.
Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene.
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DOI：
10.1186/1423-0127-17-28
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发表时间：
2010-04-20
影响因子：
11
通讯作者：
Loh HH
中科院分区：
文献类型：
--
作者：
Chen SL;Ma HI;Han JM;Lu RB;Tao PL;Law PY;Loh HH
阿片类镇痛药如吗啡和哌替啶已用于控制中度至重度疼痛多年。然而，这些阿片类药物有许多副作用，包括长期使用后的耐受性和依赖性，这限制了它们的临床应用。我们之前报道过，多阿片受体（MOR） S196L和S196A的突变使它们对阿片拮抗剂纳洛酮有反应，而不改变激动剂的表型。在MORS196A敲入小鼠中，纳洛酮和纳曲酮具有抗痛觉性，但不引起耐受性或身体依赖性。本研究将该突变的MOR基因导入疼痛相关通路，以证实在体内转染MORS196A基因并使用纳洛酮作为新型镇痛药的可能性。用MORS196A基因转染morsko小鼠脊髓，观察吗啡和纳洛酮对MORS196A基因的抑制作用。采用双链腺相关病毒2型（dsAAV2）在脊髓（S2/S3）背角区微注射，传递mors196a增强的绿色荧光蛋白（EGFP）基因。用甩尾试验测定药物的抗伤害感受作用。在基因转染前，吗啡（10mg /kg, s.c）和纳洛酮（10mg /kg, s.c）对moro - ko小鼠无抗伤害感受作用。然而，将MOR-S196A基因局部注射到MOR-KO小鼠脊髓2周或3周后，纳洛酮或吗啡可诱导明显的抗伤害感受作用。另一方面，在亚慢性治疗后，只有吗啡而非纳洛酮诱导了显著的耐受性。将MORS196A基因转染到moro - ko小鼠的脊髓中，并全身给予纳洛酮，激活外源传递的突变型MOR，并在不引起耐受性的情况下提供抗伤害性作用。由于纳洛酮不会激活正常动物或人类的天然MOR，因此与传统的阿片类激动剂相比，它的副作用更小，耐受性和依赖性也更低。
Opioid analgesics such as morphine and meperidine have been used to control moderate to severe pain for many years. However, these opioids have many side effects, including the development of tolerance and dependence after long-term use, which has limited their clinical use. We previously reported that mutations in the mu-opioid receptors (MOR) S196L and S196A rendered them responsive to the opioid antagonist naloxone without altering the agonist phenotype. In MORS196A knock-in mice, naloxone and naltrexone were antinociceptive but did not cause tolerance or physical dependence. In this study we delivery this mutated MOR gene into pain related pathway to confirm the possibility of in vivo transfecting MORS196A gene and using naloxone as a new analgesic agent. The MOR-knockout (MOR-KO) mice were used to investigate whether morphine and naloxone could show antinociceptive effects when MORS196A gene was transfected into the spinal cords of MOR-KO mice. Double-stranded adeno-associated virus type 2 (dsAAV2) was used to deliver the MORS196A-enhanced green fluorescence protein (EGFP) gene by microinjected the virus into the spinal cord (S2/S3) dorsal horn region. Tail-flick test was used to measure the antinociceptive effect of drugs. Morphine (10 mg/kg, s.c.) and naloxone (10 mg/kg, s.c.) had no antinociceptive effects in MOR-KO mice before gene transfection. However, two or three weeks after the MOR-S196A gene had been injected locally into the spinal cord of MOR-KO mice, significant antinociceptive effects could be induced by naloxone or morphine. On the other hand, only morphine but not naloxone induced significant tolerance after sub-chronic treatment. Transfecting the MORS196A gene into the spinal cord and systemically administering naloxone in MOR-KO mice activated the exogenously delivered mutant MOR and provided antinociceptive effect without causing tolerance. Since naloxone will not activate natural MOR in normal animals or humans, it is expected to produce fewer side effects and less tolerance and dependence than traditional opioid agonists do.
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影响因子：
3
作者：
Peel, AL;Klein, RL
通讯作者：
Klein, RL
影响因子：
64.8
作者：
Matthes, HWD;Maldonado, R;Kieffer, BL
通讯作者：
Kieffer, BL
影响因子：
16.2
作者：
Zhu, YX;King, MA;Pintar, JE
通讯作者：
Pintar, JE
DOI：
10.1016/s0169-328x(97)00353-7
发表时间：
1998-03-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Loh, HH;Liu, HC;Wei, LN
通讯作者：
Wei, LN
影响因子：
5.1
作者：
Wang, Z;Ma, HI;Xiao, X
通讯作者：
Xiao, X