Significance of serotonin for pain, allodynia, and hyperalgesia in the human masseter muscle

The main aim of this thesis was to investigate the hypothesis that serotonin (5-HT) is involved in the pathophysiology of human chronic muscle pain. The thesis comprises a clinical and a human experimental part. The aim for the clinical part was to investigate the level of 5-HT in the superficial masseter muscle as well as the serum and plasma levels and their relation to pain, allodynia, and hyperalgesia. The aim for the experimental part was to investigate if injection of 5-HT into the superficial masseter muscle causes pain and allodynia/hyperalgesia as well as to investigate the effect on these variables by the 5-HT antagonists granisetron and propranolol.

The clinical part comprised patients with fibromyalgia and localised myalgia (myofascial pain) of the orofacial region as well as healthy individuals. The subjects were examined for local pain and palpatory tenderness of orofacial muscles and pressure pain threshold as well as tolerance level of the superficial masseter muscle. Intramuscular microdialysis was used to sample 5-HT from the superficial masseter muscle and venous blood was collected for analysis of serum and plasma levels of 5-HT. 5-HT was found in the masseter muscle and the level was higher in the patients with fibromyalgia than in the healthy individuals. Furthermore, high level of 5-HT was associated with pain, allodynia, and hyperalgesia of the muscle. The serum level of 5-HT tended to be lower in patients with fibromyalgia than healthy individuals, while there was no difference between groups as regards plasma 5-HT level. Low serum level of 5-HT was associated with allodynia and hyperalgesia of orofacial muscles in patients with fibromyalgia and localised myalgia.

The first experimental study comprised female patients with fibromyalgia and age matched female healthy individuals. 5-HT in three different concentrations was injected at random into the masseter muscle in a double-blind manner. Isotonic saline served as control. The difference in current pain intensity and pressure pain threshold of the masseter muscle after injection compared to baseline was calculated. Pain and allodynia/hyperalgesia developed after injection of 5-HT in the healthy individuals. In the patients with fibromyalgia, there was a non-significant increase of pain after injection of 5-HT, which was not different from that after saline. Irrespective of the substance injected, the duration of the current increase of pain was longer in the patients with fibromyalgia than the duration of transient pain in the healthy individuals.

The second experimental study was performed in healthy individuals. 5-HT in combination with the 5-HT3 antagonist granisetron or the 5-HT1A antagonist propranolol was randomly and double-blindly injected into the masseter muscle. 5-HT in combination with isotonic saline served as control. The difference in pain intensity and pressure pain threshold of the masseter muscle after injection compared to baseline was calculated. Granisetron significantly attenuated pain and abolished the decrease of pressure pain threshold induced by 5-HT, while there was a weak effect on pain after injection of propranolol. This result indicates that 5-HT3 receptors are present in the human masseter muscle and might be involved in the local pathophysiology of myalgia.

List of scientific papers

I. Hedenberg-Magnusson B, Ernberg M, Kopp S (1997). Symptoms and signs of temporomandibular disorders in patients with fibromyalgia and local myalgia of the temporomandibular system. A comparative study. Acta Odontol Scand. 55(6):344-349.
https://pubmed.ncbi.nlm.nih.gov/9477026

II. Ernberg M, Hedenberg-Magnusson B, Alstergren P, Kopp S (1999). The level of serotonin in the superficial masseter muscle in relation to local pain and allodynia. Life Sci. 65(3):313-325.
https://pubmed.ncbi.nlm.nih.gov/10447217

III. Ernberg M, Hedenberg-Magnusson B, Alstergren P, Lundeberg T, Kopp S (1999). Pain, allodynia, and serum serotonin level in orofacial pain of muscular origin. J Orofac Pain. 13(1):56-62.
https://pubmed.ncbi.nlm.nih.gov/10425969

IV. Ernberg M, Voog Ü, Alstergren P, Lundeberg T, Kopp S (2000). Plasma and serum serotonin levels and their relation to orofacial pain and anxiety in fibromyalgia. J Orofac Pain. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/11203736

V. Ernberg M, Lundeberg T, Kopp S (2000). Pain and allodynia/hyperalgersia induced by intramuscular injection of serotonin into the masseter muscle in patients with fibromyalgia and healthy individuals. Pain. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/10692600

VI. Ernberg M, Lundeberg T, Kopp S (1999). Effect of granisteron and propranolol on exerimentally induced pain and allodynia/hyperalgesia by intramuscular injection of serotonine into the human masseter muscle. Pain. [Accepted]
https://pubmed.ncbi.nlm.nih.gov/10666539