Abstract
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 HTR3A (rs1062613) and HTR3B (rs1176744). 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 (HTR3A) (P = 0.015) and pain intensity higher in women with the A/C alleles (HTR3B) (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 (HTR3A) genotype had less reduction of pain intensity (P = 0.041) and area (P = 0.005), and women with the C/C genotype (HTR3B) 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.
Highlights
Pain is described as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (International Association for the Study of Pain) [1]
Results indicate that release of inflammatory substances, such as serotonin (5-HT) may be involved at a peripheral level. 5-HT is a monoamine that derives from tryptophan and serves as a neurotransmitter. 5-HT is found both in the peripheral nervous system (PNS) and in the central nervous system (CNS) and participates in pain amplification as well as in pain inhibition in the serotonergic system depending which receptor subtype it activates [8]
HTR3A and HTR3B polymorphisms have been shown to serve as predictors for the effectiveness of 5-HT3 antagonists [27] as well as the antidepressant response to the serotonin selective reuptake inhibitor paroxetine [36]. Taken together these findings indicate that genetic variants in the HTR3A and HTR3B may be involved in the pathophysiology of depressive disorders and the clinical effect of 5-HT3 antagonists
Summary
Pain is described as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (International Association for the Study of Pain) [1]. One type of chronic pain condition in the orofacial area is temporomandibular disorder (TMD) It affects approximately 10–15% of the adult population [2, 3] and is twice as common in women as men [4, 5]. Previous studies have reported increased masseter muscle levels of 5-HT in patients with chronic myalgia and a positive correlation to muscle pain and tenderness [11, 12]. Experimental studies have shown that local administration of drugs that block 5-HT3 receptors, such as granisteron, have a pain reducing analgesic effect and increase the pressure pain threshold (PPT) in TMD myalgia [17] as well as after experimentally induced pain in the masseter muscle in healthy subjects [18, 19]. Two other studies reported increased PPT only in the men, both after oral and local administration of granisetron [18, 20]
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