Genetic studies have become indispensable in understanding pain mechanisms, shedding light on the role of monoamine pathways in pain modulation. The present study was aimed to explore the relationship between functional polymorphisms in serotonin and dopamine-related genes and pain modulation. Two paradigms of pain modulation were administered to 191 healthy participants in a random order: Conditioned Pain Modulation in response to painful stimuli (CPM_painful) tested by the coadministration of repeated short painful heat stimuli and a conditioning tonic cold pain stimulation; and Conditioned Pain Modulation in response to nonpainful stimuli (CPM_nonpainful) tested similarly, except for using a painless conditioning stimulation. Using the Transmission Disequilibrium Test (TDT), functional variable number of tandem repeat (VNTR) polymorphisms of the following candidate genes were studied: 1) serotonin transporter (5-HTTLPR); 2) dopamine transporter (DAT1); 3) dopamine receptor 4 (DRD4); and 4) monoamine oxidase A (MAOA). DNA samples from both participants and their parents were analyzed. A significant association was found between CPM_nonpainful and the 5-HTTLPR polymorphism (P = .001). More specifically, carriers of the long allele exhibited a significantly higher magnitude of CPM_nonpainful than carriers of the short allele. No associations were found between the dopamine-related genes and both types of pain modulation. These results highlight the importance of serotonin in endogenous analgesia.

This article presents an association between the serotonin transporter gene polymorphism (5-HTTLPR) and pain modulation derived by nonpainful conditioned pain modulation (CPM_nonpainful), rather than painful conditioned pain modulation (CPM_painful). These findings emphasize the complex role of serotonin in pain modulation, and highlight the importance of genetic studies in the understanding of interindividual differences in sensitivity to pain.