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.
Highlights
Catechol O-methyltransferase (COMT) is an enzyme that has been implicated in the perception of mechanical, thermal, and inflammatory pain in both humans and rodents [1,2,3]
Serotonin Binds to COMT Binding interactions between serotonin and COMT were determined through surface plasmon resonance (Figure 1B) whereby both the rate of association and dissociation can be determined
We find that serotonin dissociates from COMT with a koff rate of 0.0012 s-1, and binds to COMT with a kon rate of 13.7404 M-1 s-1
Summary
Catechol O-methyltransferase (COMT) is an enzyme that has been implicated in the perception of mechanical, thermal, and inflammatory pain in both humans and rodents [1,2,3]. Its association with a broad range of noxious stimuli suggests its critical role as an underlying factor for the fundamental processes of pain perception. Compounds or cellular regulatory factors that lower COMT activity enhance pain sensation. While commonly associated with antinociception [5,6], serotonin (5-hydroxytryptamine, or 5-HT) is known to produce a hyperalgesic response when injected subcutaneously or into deep tissue [7,8]. Different subtypes of 5-HT receptors are associated with hypersensitive responses to
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