Douglas Tsao - Serotonin-induced hypersensitivity via inhibition of catechol O-methyltransferase activity

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      Tsao, D., Wieskopf, J. S., Rashid, N., Sorge, R. E., Redler, R.   L., Segall, S. K., Mogil, J. S., Maixner, W., Dokholyan, N. V.   and Diatchenko, L., Molecular Pain, 8:25, (2012)


      The   subcutaneous and systemic injection of serotonin reduces   cutaneous and visceral pain thresholds and increases responses to   noxious stimuli. Different subtypes of 5-hydroxytryptamine (5-HT)   receptors are suggested to be associated with different types of   pain responses. Here we show that serotonin also inhibits   catechol O-methyltransferase (COMT), an enzyme that contributes   to modultion the perception of pain, via non-competitive binding   to the site bound by catechol substrates with a binding affinity   comparable to the binding affinity of catechol itself (Ki = 44   uM). Using computational modeling, biochemical tests and cellular   assays we show that serotonin actively competes with the methyl   donor S-adenosyl-L-methionine (SAM) within the catalytic site.   Binding of serotonin to the catalytic site inhibits the access of   SAM, thus preventing methylation of COMT substrates. The results   of in vivo animal studies show that serotonin-induced pain   hypersensitivity in mice is reduced by either SAM pretreatment or   by the combined administration of selective antagonists for B2-   and B3-adrenergic receptors, which have been previously shown to   mediate COMT-dependent pain signaling. Our results suggest that   inhibition of COMT via serotonin binding contributes to pain   hypersensitivity, providing additional strategies for the   treatment of clinical pain conditions.

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