Serotonin-Induced Hypersensitivity via Inhibition of Catechol O-Methyltransferase Activity
1 Department of Chemistry University of North Carolina, Chapel Hill, NC 27599, USA
2 Center for Neurosensory Disorders, University of North Carolina, Chapel Hill, NC 27599, USA
3 Department of Psychology, McGill University, 1205 Dr. Penfield Avenue, Montreal, QC, H3A 1B1, Canada
4 Department of Biostatistics Gillings School of Global Public Health University of North Carolina, Chapel Hill, NC 27599, USA
5 Department of Biochemistry and Biophysics, School of Medicine University of North Carolina, Chapel Hill, NC 27599, USA
Molecular Pain 2012, 8:25 doi:10.1186/1744-8069-8-25Published: 13 April 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 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.