The 5-HT3 blocker granisetron reduces muscle pain induced by hypertonic saline

Objectives: Intramuscular injections with hypertonic saline are frequently used as induction of experimental pain that mimics chronic muscle pain (myalgia). 5-HT, a neurotransmitter, participates in the pain mediation via the 5-HT3 receptor. Granisetron, a selective 5-HT3-receptor antagonist, has previously been reported to increase the pressure pain threshold (PPT) in healthy muscles and to reduce hyperalgesia in patients with local myalgia. The aim of this study was to investigate whether the specific 5-HT3 receptor antagonist granisetron influences the pain induced by an intramuscular injection of hypertonic saline in the masseter muscle on healthy females. Material and methods: This study comprised 13 healthy females with a mean (SD) age of 26 (3.3) years. The participating subjects were undergraduate dental students at the Institute of Odontology, Karolinska Institutet. This experimental study was based on a randomized, placebo-controlled, double-blind model. All subjects received two bilateral injections in the masseter muscle with hypertonic saline and one injection of granisetron on one side and isotonic saline on the contra lateral side. The subjects were asked to score their pain intensity on a visual analogue scale (VAS) immediately after the two injections of hypertonic saline and every 15 seconds until pain subsided totally. The PPT was recorded twice at each site every 5 minute after injection of the test substances. Results: The first injection of hypertonic saline induced pain of similar intensity and duration on both sides, while the second injection of hypertonic saline induced considerably less pain after pre-injection with granisetron, than after pre-injection with isotonic saline. The PPT did not change significantly on any side after injection of hypertonic saline and there were no significant differences between sides. Conclusion: Granisetron clearly lowers the pain induced by hypertonic saline in healthy female subjects and the pain response tenders to be shorter after injection of granisetron. Introduction Intramuscular injections with hypertonic saline are frequently used as experimental pain initiators. This is an exogenous muscle pain model that activates muscle nociceptors and causes a dominant sensation of deep, diffuse pain which is similar to chronic myalgia (1, 2, 3). The safety of this experimental design, without any side effects is a major reason for the use of hypertonic saline in experimental pain studies (4). Hypertonic saline has further been suggested to directly stimulate muscle nociceptors by excitation of group III and IV muscle afferents and central neurons encoding nociceptive information as well as glutamate release (1, 5). It has been shown that bradykinin, serotonin (5-HT) and glutamate, that are inflammatory mediators and algesic substances (3, 6, 7, 8) induces plastic changes in the brain steam by central sensitization and contributes to allodynia and hyperalgesia (9, 10, 11, 12). Kiriaki Ioannidou, Milena Milosevic 380 Muscle nociceptors are free nerve endings supplied by group III and IV afferents and can be sensitized to chemical and mechanical stimuli. By applying moderate to intense pressure on human muscle tissue, high-threshold mechanosensitive (HTM) receptors are activated (13). Most of these receptors are polymodal receptors, which mean that they normally respond to a variety of stimuli including algesic chemical stimulation such as intramuscular injection of hypertonic saline (9, 10). 5-HT is a neurotransmitter and neuromodulator found in platelets, the enterochromaffin cells, and in certain regions of the brain (14). It participates in the pain mediation via the 5HT3 receptor (15, 16) on the afferent sensory and sympathetic nerves and is released from platelets due to tissue damage or ischemia (9, 17). Several 5-HT3 receptor antagonists have been used in previous studies that have shown that systemic administration of 5-HT3antagonists reduce pain and hyperalgesia in patients with fibromyalgia (18, 19, 20). It has been reported that the pressure pain threshold (PPT) in healthy muscles was increased after systemic administration of the selective 5-HT3-antagonist which indicates that 5-HT play a role in determining the PPT in muscle tissue (21). Furthermore, a study by Ernberg et al. (2000) showed that 5-HT induced pain and allodynia in the masseter muscle of healthy women only. The pain and allodynia induced by the injection of 5-HT was reduced after local administration of the 5-HT3-antagonist granisetron. In other studies, the 5-HT3-antagonist tropisetron reduced clinical pain in patients with tendinopathies, low back pain and myofascial pain (22, 23, 24). The aim of his study was to investigate whether the specific 5-HT3 receptor antagonist granisetron influences the pain induced by an intramuscular injection of hypertonic saline in the masseter muscle on healthy females. Material and methods Subjects This study comprised 13 healthy females with a mean (SD) age of 26 (3.29) years. The participating subjects were undergraduate dental students at the Institute of Odontology, Karolinska Institutet. They were included if they were over 18 years of age, had good general health, had no pain from the orofacial region but minor tenderness to palpation of the masticatory muscles. Use of any analgesic medication during the day of study and/or a history of allergic reactions to granisetron led to exclusion. The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee (KI/Syd) at Karolinska University Hospital, Karolinska Institutet, Huddinge, Sweden (233/03) and by the Medical Products Agency in Uppsala, Sweden. All subjects received both verbal and written information and gave their written consent.