Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene

Journal of Biomedical Science

Research

Jun-Ming Han¹  Hsin-I Ma¹  Pao-Luh Tao²  Ping-Yee Law³  Horace H Loh³  Ru-Band Lu⁴  Shiou-Lan Chen⁴ 

[1] Department of Neurosurgery, Tri-Service General Hospital, Taipei, Taiwan;Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan;Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA;Department of Psychiatry, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan;

关键词: Morphine;    Naloxone;    Naltrexone;    Antinociceptive Effect;    Opioid Antagonist;   

DOI  :  10.1186/1423-0127-17-28

 received in 2010-02-10, accepted in 2010-04-20,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundOpioid 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.MethodsThe 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.ResultsMorphine (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.ConclusionTransfecting 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.

【 授权许可】

Unknown   
© Chen et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.