- 作者: Shiou-Lan Chen; Hsin-I Ma; Jun-Ming Han; Ru-Band Lu; Pao-Luh Tao; Ping-Yee Law; Horace H Loh
- 作者服務機構: Department of Psychiatry, College of Medicine and Hospital, National Cheng Kung University, Tainan, Taiwan, R.O.C.
- 中文摘要: --
- 英文摘要:
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 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.
Conclusion : 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. - 中文關鍵字: --
- 英文關鍵字: --