Abstract
The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC50: 5.29, 7.91, and 4.08 μM, respectively. These values were similar to the IC50 value at BGT-1 (10.6 μM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.
| Original language | English |
|---|---|
| Pages (from-to) | 217-226 |
| Number of pages | 10 |
| Journal | Journal of Pharmacological Sciences |
| Volume | 125 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2014 |
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Keywords
- Antiallodynic action
- Betaine/GABA transporter
- Monoamine transporter
- Neuropathic pain
- NNC05-2090
ASJC Scopus subject areas
- Pharmacology
- Molecular Medicine
- Medicine(all)
Cite this
Antiallodynic action of 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2- methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor. / Jinzenji, Ayako; Sogawa, Chiharu; Miyawaki, Takuya; Wen, Xue Fang; Yi, Dan; Ohyama, Kazumi; Kitayama, Shigeo; Sogawa, Norio; Morita, Katsuya.
In: Journal of Pharmacological Sciences, Vol. 125, No. 2, 2014, p. 217-226.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antiallodynic action of 1-(3-(9H-carbazol-9-yl)-1-propyl)-4-(2- methyoxyphenyl)-4-piperidinol (NNC05-2090), a betaine/GABA transporter inhibitor
AU - Jinzenji, Ayako
AU - Sogawa, Chiharu
AU - Miyawaki, Takuya
AU - Wen, Xue Fang
AU - Yi, Dan
AU - Ohyama, Kazumi
AU - Kitayama, Shigeo
AU - Sogawa, Norio
AU - Morita, Katsuya
PY - 2014
Y1 - 2014
N2 - The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC50: 5.29, 7.91, and 4.08 μM, respectively. These values were similar to the IC50 value at BGT-1 (10.6 μM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.
AB - The GABAergic system in the spinal cord has been shown to participate in neuropathic pain in various animal models. GABA transporters (GATs) play a role in controlling the synaptic clearance of GABA; however, their role in neuropathic pain remains unclear. In the present study, we compared the betaine/GABA transporter (BGT-1) with other GAT subtypes to determine its participation in neuropathic pain using a mouse model of sciatic nerve ligation. 1-(3-(9H-Carbazol-9-yl)-1-propyl)-4-(2-methyoxyphenyl)-4-piperidinol (NNC05-2090), an inhibitor that displays moderate selectivity for BGT-1, had an antiallodynic action on model mice treated through both intrathecally and intravenous administration routes. On the other hand, SKF89976A, a selective GAT-1 inhibitor, had a weak antiallodynic action, and (S)-SNAP5114, an inhibitor that displays selectivity for GAT-3, had no antiallodynic action. Systemic analysis of these compounds on GABA uptake in CHO cells stably expressing BGT-1 revealed that NNC05-2090 not only inhibited BGT-1, but also serotonin, noradrenaline, and dopamine transporters, using a substrate uptake assay in CHO cells stably expressing each transporter, with IC50: 5.29, 7.91, and 4.08 μM, respectively. These values were similar to the IC50 value at BGT-1 (10.6 μM). These results suggest that the antiallodynic action of NNC05-2090 is due to the inhibition of both BGT-1 and monoamine transporters.
KW - Antiallodynic action
KW - Betaine/GABA transporter
KW - Monoamine transporter
KW - Neuropathic pain
KW - NNC05-2090
UR - http://www.scopus.com/inward/record.url?scp=84903981995&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903981995&partnerID=8YFLogxK
U2 - 10.1254/jphs.13146FP
DO - 10.1254/jphs.13146FP
M3 - Article
VL - 125
SP - 217
EP - 226
JO - Journal of Pharmacological Sciences
JF - Journal of Pharmacological Sciences
SN - 1347-8648
IS - 2
ER -