In:
Pharmacology, S. Karger AG, Vol. 77, No. 2 ( 2006), p. 93-99
Abstract:
〈 i 〉 Purpose: 〈 /i 〉 Tramadol is widely used clinically as an analgesic, yet the mechanism by which it produces antinociception remains unclear. O-Desmethyl tramadol, the main metabolite of tramadol, is a more potent analgesic than tramadol. We reported previously that tramadol inhibits the 5-hydroxytryptamine (5-HT) type 2C receptor (5-HT 〈 sub 〉 2C 〈 /sub 〉 R), a G-protein-coupled receptor that is expressed widely within brain and that mediates several effects of 5-HT, including nociception, feeding, and locomotion. The effects of O-desmethyl tramadol on 5-HT 〈 sub 〉 2C 〈 /sub 〉 R have not been studied. In this study, we investigated the effect of O-desmethyl tramadol on 5-HT 〈 sub 〉 2C 〈 /sub 〉 R expressed in 〈 i 〉 Xenopus 〈 /i 〉 oocytes. 〈 i 〉 Methods: 〈 /i 〉 We examined the effect of O-desmethyl tramadol on 5-HT 〈 sub 〉 2C 〈 /sub 〉 R using the 〈 i 〉 Xenopus 〈 /i 〉 oocyte expression system. Furthermore, we investigated the effects of O-desmethyl tramadol on the binding of [ 〈 sup 〉 3 〈 /sup 〉 H]5-HT by 5-HT 〈 sub 〉 2C 〈 /sub 〉 R. 〈 i 〉 Results: 〈 /i 〉 O-Desmethyl tramadol, at pharmacologically relevant concentrations, inhibited 5-HT-evoked Ca 〈 sup 〉 2+ 〈 /sup 〉 -activated Cl 〈 sup 〉 – 〈 /sup 〉 currents in oocytes that expressed 5-HT 〈 sub 〉 2C 〈 /sub 〉 R. The inhibitory effect of O-desmethyl tramadol on 5-HT 〈 sub 〉 2C 〈 /sub 〉 R was overcome at higher concentrations of 5-HT. Bisindolylmaleimide I (GF109203X), a protein kinase C inhibitor, increased 5-HT-evoked currents but had little effect on the inhibition of 5-HT-evoked currents by O-desmethyl tramadol. O-Desmethyl tramadol inhibited the specific binding of [ 〈 sup 〉 3 〈 /sup 〉 H]5-HT by 5-HT 〈 sub 〉 2C 〈 /sub 〉 R expressed in oocytes. O-Desmethyl tramadol altered the apparent dissociation constant for binding of [ 〈 sup 〉 3 〈 /sup 〉 H]5-HT by 5-HT 〈 sub 〉 2C 〈 /sub 〉 R without changing maximum binding, which indicated competitive inhibition. 〈 i 〉 Conclusion: 〈 /i 〉 These results suggest that O-desmethyl tramadol inhibits 5-HT 〈 sub 〉 2C 〈 /sub 〉 R, which provides further insight into the pharmacological properties of tramadol and O-desmethyl tramadol.
Type of Medium:
Online Resource
ISSN:
0031-7012
,
1423-0313
Language:
English
Publisher:
S. Karger AG
Publication Date:
2006
detail.hit.zdb_id:
1483550-2
SSG:
15,3
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