Pain mechanisms and the genetic influence of 5-HTT and OPRM1 polymorphisms

Abstract

Previous studies indicate that central sensitization may be an underlying mechanism of hyperalgesia and development of persistent pain. However, some individuals may have a higher risk of long lasting pain than others, which may be associated with genetic variation.

In the present study we examined pain sensitization in both healthy volunteers and disc herniation patients. In the healthy volunteers we used electrical high frequency stimulation (HFS) to induce experimental hyperalgesia, and the sensitization was measured by visual analogue scale (VAS) pain ratings for a short period of time, i.e. 25 min. In the disc herniation patients, data on both VAS pain ratings and pressure pain thresholds (PPTs) were sampled for a longer period of time, i.e. one year. To investigate if the sensitization was associated with individual genetic variations, both the healthy volunteers and the patients were genotyped regarding two genes possibly important for pain modulation, i.e. the serotonin transporter (5-HTT) and the opioid receptor mu 1 (OPRM1). In accordance with earlier studies the 5-HTT genotypes were defined as low 5-HTT and high 5-HTT based on the transcription rate, whereas the µ-opioid receptor genotypes were defined as AA and AG/GG where the G allele may affect the function of the protein. In addition, to examine the effect of nucleus pulposus (NP) from the intervertebral discs after disc herniation, NP was, in a rat model, applied onto the afferent dorsal nerve roots, and single cell recordings of spinal wide dynamic range (WDR) neurons were performed in the dorsal horn.

The results did not show any significant association between the degree of experimental hyperalgesia in healthy volunteers and the 5-HTT or the OPRM1 genotypes. Furthermore, the present data did not indicate any convincing associations between the disc herniation patients’ VAS pain ratings and the variability of the 5-HTT or the OPRM1 genes. However, the findings of this study demonstrated a significant association between the PPTs of the patients and the 5-HTT and OPRM1 genotypes; individuals with high 5-HTT or individuals with AA OPRM1 genotype were more sensitive to pain than others. The animal experiments showed that NP applied onto the afferent dorsal nerve roots induced a significant increase in the C-fibre responses in the spinal dorsal horn.

Taken together, our data showed that pain sensitization can be induced by electrical HFS conditioning, but did not reveal any clear associations between experimental pain sensitization and the genetics of the 5-HTT or OPRM1. However, the present findings demonstrated that the pain sensitivity, measured by PPTs, in disc herniation patients, may be affected by genetic variability in the genes encoding the 5-HTT and OPRM1. Furthermore, based on the animal experiments, it seems likely that NP from herniated discs may be an important factor for the enhanced pain. It is concluded that differences in pain sensitivity may be associated with genetic variation in the 5-HTT and OPRM1 genes encoding the serotonin transporter and the µ-opioid receptor, respectively.