Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase ActivityReport as inadecuate




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Molecular Pain

, 8:25

First Online: 13 April 2012Received: 12 January 2012Accepted: 27 March 2012

Abstract

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 μM. 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 β2- and β3-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.

Electronic supplementary materialThe online version of this article doi:10.1186-1744-8069-8-25 contains supplementary material, which is available to authorized users.

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Author: Douglas Tsao - Jeffrey S Wieskopf - Naim Rashid - Robert E Sorge - Rachel L Redler - Samantha K Segall - Jeffrey S Mog

Source: https://link.springer.com/







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