Influence of Polymorphisms in the <i>HTR3A</i> and <i>HTR3B</i> Genes on Experimental Pain and the Effect of the 5-HT₃ Antagonist Granisetron

<div><p>The aim of this study was to investigate experimentally if 5-HT₃ single nucleotide polymorphisms (SNP) contribute to pain perception and efficacy of the 5-HT₃-antagonist granisetron and sex differences. Sixty healthy participants were genotyped regarding <i>HTR3A (rs1062613)</i> and <i>HTR3B (rs1176744)</i>. First, pain was induced by bilateral hypertonic saline injections (HS, 5.5%, 0.2 mL) into the masseter muscles. Thirty min later the masseter muscle on one side was pretreated with 0.5 mL granisetron (1 mg/mL) and on the other side with 0.5 mL placebo (isotonic saline) followed by another HS injection (0.2 mL). Pain intensity, pain duration, pain area and pressure pain thresholds (PPTs) were assessed after each injection. HS evoked moderate pain, with higher intensity in the women (P = 0.023), but had no effect on PPTs. None of the SNPs influenced any pain variable in general, but compared to men, the pain area was larger in women carrying the C/C (<i>HTR3A</i>) (P = 0.015) and pain intensity higher in women with the A/C alleles (<i>HTR3B</i>) (P = 0.019). Pre-treatment with granisetron reduced pain intensity, duration and area to a lesser degree in women (P < 0.05), but the SNPs did not in general influence the efficacy of granisetron. Women carrying the C/T & T/T (<i>HTR3A</i>) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (<i>HTR3B</i>) had less reduction of pain intensity (P = 0.030), duration (P = 0.030) and area compared to men (P = 0.017). In conclusion, SNPs did not influence experimental muscle pain or the effect of granisetron on pain variables in general, but there were some sex differences in pain variables that seem to be influenced by genotypes. However, due to the small sample size further research is needed before any firm conclusions can be drawn.</p></div

Pain variables after pretreatment with granisetron after the second injection of hypertonic saline.

<p>Pain variables after pretreatment with granisetron after the second injection of hypertonic saline.</p

Pain distribution in the masseter muscle after HS injection alone and after pre-treatment with granisetron.

<p>The figures show the pain distribution in the masseter muscle after injections of hypertonic saline (HS) alone (first injection) and after pre-treatment with granisetron (0.5 mL) and placebo (0.5 mL isotonic saline) followed by a second injection of hypertonic saline (second injection) in 60 healthy participants (30 women and 30 age-matched men). The pain area after HS injection did not differ significantly between sexes. The pain area was significantly smaller after pre-treatment with granisetron (P < 0.001) with greater reduction in men than women (P = 0.007).</p

The distribution of the 5-HT₃-polymorphisms <i>HTR3A</i> (rs1062613) and <i>HTR3B</i> (rs1176744).

<p>The distribution of the 5-HT₃-polymorphisms <i>HTR3A</i> (rs1062613) and <i>HTR3B</i> (rs1176744).</p

Flow chart of the experimental setting.

<p>The figure shows the time points (minutes) for the clinical examination, blood sampling, assessment of pain intensity (VAS), pressure pain thresholds (PPT), time points for injections and pain drawings. At the time point 0 minutes, bilateral injections of hypertonic saline (0.2 mL) into the masseter muscles were performed. At the time point 31 minutes, pre-treatment with granisetron (0.5 mL) on one side of the masseter muscle and placebo (0.5 mL) on the other side was done. Two minutes later, a second bilateral injection of hypertonic saline (0.2 mL) was performed. Pain intensity, pain duration and pain area were assessed after each injection.</p

Pain variables after injection of hypertonic saline.

<p>Pain variables after injection of hypertonic saline.</p