Peripheral Serotonin Enhances Orofacial Nocifensive Behavior in Female Rats at Lower Doses During Proestrus

Abstract

Trigeminal pain, such as migraine and temporomandibular joint disorder pain, disproportionately affects women, however the mechanism underlying this dimorphic prevalence is unclear. One pain mechanism that may be modulated by gonadal hormones is the ability of the neurotransmitter serotonin (5HT) to lower pain thresholds. 5HT is a pronociceptive mediator in the periphery where it is stored and released by platelets and immune cells (e.g. mast cells, T‐cells, dendritic cells). The pronociceptive role of 5HT is well‐known in males, however 5HT may be under modulation by gonadal hormones in females. We recently reported that 5HT, injected into the hind paw, evoked greater, longer‐lasting pain behaviors in female rats during proestrus and estrus (dramatic fluctuations in hormones) compared to females in diestrus (steady low hormones), males, and ovariectomized (OVX) females. Further, when injected into the vibrissal pad, 5HT only evoked orofacial pain behaviors in females in proestrus and estrus. As 5HT receptors are colocalized with the transient receptor potential vanilloid 1 ion channel (TRPV1), a cation channel activated by capsaicin that initiates pain signaling, it is possible that 5HT differentially potentiates TRPV1 activity leading to our observed sex differences and estrous cycle effects. We hypothesized that 5HT potentiates capsaicin‐evoked orofacial nocifensive behaviors to a greater degree when hormones are in flux. Rats were acclimated and 24 hours later received a 50 μl injection of 1.5 μg 5HT + 1 μg capsaicin, 3 μg 5HT + capsaicin, or capsaicin only into the vibrissal pad (n=6–9 per group) and orofacial nocifensive behaviors were scored as number of forelimb swipes at the injection site in 6 min bouts over 30 min. We report that rats in proestrus exhibited significant nocifensive behaviors following injection of both the lower and higher doses of 5HT with capsaicin compared to capsaicin alone. Females in estrus and males exhibited significant nocifensive behaviors only following the higher 5HT dose with capsaicin. No significant effect of 5HT on capsaicin‐evoked pain behavior was observed in OVX females or females in diestrus. We also tested whether there were differences in 5HT content in the interstitial fluid of rodent vibrissal pads following 24 hours of inflammation. Rats received a left vibrissal pad injection of 50 μl complete Freund's adjuvant (CFA) and a right vibrissal pad injection of saline. After 24 hours, punch biopsies were collected and centrifuged to obtain interstitial fluid and 5HT content was quantified by ELISA. Males had significantly less serotonin content than cycling females in the saline‐injected vibrissal pads. When CFA elevated the 5HT content, a sex difference was no longer detected. Together our data indicate that serotonin may be enhancing TRPV1 activity at subthreshold doses when estrogen is high. Estrogen exacerbation of serotonergic pain in trigeminal sensory neurons combined with greater basal levels of serotonin in orofacial tissues may be one contributing factor to the greater prevalence of trigeminal disorders in women.Support or Funding InformationThis research is supported by NIH NIDCR R15DE025970 awarded to DLA. This study was also, in part, supported by TWU Research Enhancement Grants and a Chancellor's Research Fellowship.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.