The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1.
BACKGROUND
Tramadol is an effective analgesic substance widely used in medical practice. Its therapeutic action have been mainly attributed to the activation of mu-opioid receptors as well as to the inhibition of neurotransmitter reuptake mechanisms and various voltage- and ligand-gated ion channels of the nociceptive system. As transient receptor potential vanilloid-1 (TRPV1, "the capsaicin receptor") has been shown to function as a central integrator molecule of pain sensation, our aim in the current study was to define the involvement of TRPV1 in the complex mechanism of action of tramadol.


METHODS
To achieve these goals, we used single-cell Ca-imaging as well as fluorescent image plate reader assays on Chinese hamster ovary (CHO) cells heterologously over-expressing TRPV1.


RESULTS
We found that (1) tramadol, similar to the well-known TRPV1 agonist, capsaicin, significantly increased [Ca(2+)](i) of TRPV1-CHO cells in a concentration-dependent fashion; (2) its effect was reversibly prevented by the TRPV1 antagonist capsazepine; (3) repeated application of tramadol resulted in marked tachyphylaxis; and (4) tramadol did not modify [Ca(2+)](i) in control (empty vector expressing) CHO cells.


CONCLUSIONS
Collectively, these findings strongly support the intriguing and novel concept that tramadol acts as an agonist of TRPV1. Considering that activation of TRPV1 on sensory neurons is followed by a local release of vasoactive neuropeptides and a marked desensitization of the afferent fibers (hence termination of pain sensation), our findings may equally explain both the desired analgesic as well as the often-seen, yet "unexpected," local side effects (e.g., initiation of burning pain and erythema) of tramadol.
Marincsák
Rita
R
Department of Physiology, University of Debrecen, Medical and Health Science Center, Research Center for Molecular Medicine, 4032 Debrecen, Hungary.
Tóth
Balázs I
BI
Czifra
Gabriella
G
Szabó
Tamás
T
Kovács
László
L
Bíró
Tamás
T
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003592:Cytophotometry; D004305:Dose-Response Relationship, Drug; D050916:TRPV Cation Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013618:Tachyphylaxis; D014147:Tramadol / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
D000701:Analgesics, Opioid; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014147:Tramadol; C071423:capsazepine; D002211:Capsaicin; D002118:Calcium