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Serotonin enhances CGRP release from female human trigeminal nociceptors

      Migraine, a pain disorder mediated by the trigeminal system, is often treatment resistant and more prevalent in women. The neurotransmitter serotonin (5HT) has been implicated in many trigeminal pain states and therapeutics targeting the 5HT system are successful in treating migraine. Trigeminal pain is often evoked by the transient receptor potential V1 channel (TRPV1), which is expressed by nociceptive trigeminal neurons and induces release of proinflammatory calcitonin gene-related peptide (CGRP). While 5HT attenuates central nociceptive processing, it is pronociceptive in the periphery. In our preclinical models, 5HT evokes thermal hyperalgesia and enhances CGRP release from trigeminal nociceptors. Whether this effect is similar in humans is unknown as no study has evaluated the pharmacology of 5HT on human nociceptors. As dental pulp is densely innervated by trigeminal nociceptors, routine tooth extractions offer a unique opportunity to examine whether 5HT enhances CGRP release from human nociceptors. Pulpal tissue was collected from extracted molar teeth from male and female patients between the ages of 14 and 35 visiting the UT Health Science Center. Following an in vitro superfusion protocol, tissue was washed in buffered saline and basal release samples were collected. Tissue was then treated with saline (n=35) or 100 μM 5HT (n=36) followed by the TRPV1 agonist capsaicin (1 μM) and CGRP release was measured by human CGRP enzyme immunoassay. Additional samples were collected to examine anatomical 5HT receptor expression. We report that 5HT induced a significant increase in CGRP release compared to vehicle controls. In addition, we found that 5HT-induced CGRP release was limited to female trigeminal nociceptors, while there was no significant effect of 5HT in males. These results indicate that 5HT enhances CGRP release from female but not male human trigeminal nociceptors and may provide a mechanistic basis for prevalence of trigeminal pain disorders, such as migraine, in women.