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

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 muopioid 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. | Chen et al. Journal of Biomedical Science 2010 17 28 http www.jbiomedsci.eom content 17 1 28 a NSC Tha cost of publication In Journal of Blomodlcal Science Is bome by tlM National Science Council Taiwan JOURNAL OF BIOMEDICAL SCIENCE RESEARCH Open Access Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene Shiou-Lan Chen1 Hsin-I Ma2 Jun-Ming Han2 Ru-Band Lu1 Pao-Luh Tao 3 Ping-Yee Law4 and Horace H Loh4 Abstract Background 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. Methods 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. Results 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 .