Hyperalgesic effects of gamma-aminobutyric acid transporter I in mice.
The present study focused on the involvement of gamma-aminobutyric acid transporter I (GAT1) in pain. We found that GABA uptake was increased in mouse spinal cord at 20 min and 120 min after formalin injection and in mouse brain at 120 min, but not 20 min, after formalin injection. In addition, the antinociceptive effects of GAT1-selective inhibitors were examined using assays of thermal (tail-flick) and chemical (formalin and acetic acid) nociception in C57BL/6J mice. The GAT1-selective inhibitors, ethyl nipecotate and NO-711, exhibited significant antinociceptive effects in these nociceptive assays. To study further the effects of GAT1 on pain, we used two kinds of GAT1-overexpressing transgenic mice (under the control of a CMV promoter or a NSE promoter) to examine the nociceptive responses in these mice. In the thermal, formalin, and acetic acid assays, both kinds of transgenic mice displayed significant hyperalgesia after nociceptive stimuli. In addition, the micro opioid receptor antagonist naloxone had no influence on nociceptive responses in wild-type and transgenic mice. The results indicate that GAT1 is involved in the regulation of pain processes, and point to the possibility of developing analgesic drugs that target GAT1 other than opioid receptors.
Hu
Jia-Hua
JH
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China.
Yang
Na
N
Ma
Ying-Hua
YH
Zhou
Xiao-Gang
XG
Jiang
Jie
J
Duan
Shu-Hui
SH
Mei
Zhen-Tong
ZT
Fei
Jian
J
Guo
Li-He
LH
D000701:Analgesics, Opioid / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005557:Formaldehyde / Q000009:adverse effects; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D027361:Organic Anion Transporters; D010091:Oximes / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013116:Spinal Cord / Q000378:metabolism; D019966:Substance-Related Disorders / Q000378:metabolism; D013574:Synaptosomes / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000701:Analgesics, Opioid; D002352:Carrier Proteins; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; D012333:RNA, Messenger; C493414:Slc6a1 protein, mouse; C078793:NNC 711; D005557:Formaldehyde; C038002:nipecotic acid ethyl ester; D005680:gamma-Aminobutyric Acid; D009020:Morphine