REGULATION OF TRPV1 ACTIVITIES BY A SEXUALLY DIMORPHIC MECHANISM

Numerous studies indicate that women and men differ in prevalence of pain disorders or pain intensity,possibly due to sexually dimorphic differences in detection, processing or responses to noxious stimuli. Here,we propose to study a peripheral sexually dimorphic pain mechanism that occurs in humans. The importanceof this complex problem has been emphasized by recent NIH policies (NOT OD 15-102). The objective hereis to determine the effects of serotonin (5HT), applied to dental pulp biopsies from women versus men, onactivation of capsaicin-sensitive nociceptors, and the mechanisms mediating this response.Our central hypothesis is that 5-HT preferentially releases complement peptides C3a or C5a from peripheraltissues of women compared to men, leading to a sexually dimorphic increase in TRPV1 activities intrigeminal (TG) sensory neurons. This central hypothesis is based on substantial novel preliminary datademonstrating that 5HT produces a sexually dimorphic difference in capsaicin activation of humanpeptidergic fibers via release of complement peptides. The Aims will:Specific Aim #1: Determine the cell type expressing C3a, C5a, C3aR, & C5aR in female versus male humandental pulp. Additional studies will determine the effects of inflammation (irreversible pulpitis) on expressionand release of C3a and C5a from female and male human tissues.Specific Aim #2: Determine the 5-HT receptor subtype(s) and G-protein and effector signaling pathwaysmediating 5-HT-evoked release of C3a and C5a from female and male human tissues.Specific Aim #3: Determine the receptors, G-protein and effector signaling pathways mediating C3a-andC5a-evoked increase in activities of capsaicin-sensitive neurons. The central hypothesis is highly innovative and, if supported, would have an important positive impact on thefield since it supports a new model for sexually dimorphic pain mechanisms with therapeutic implications.Moreover, the use of isolated human tissue biopsies and primary neuronal cultures fosters studies on thecellular mechanisms mediating this sexually dimorphic effect and increases translational significance.RELEVANCE (See instructions):Women often experince greater intensity or frequency of pain disorders. While there are likely manymechanisms mediating this effect, comparatively little research has focused on peripheal mechanisms. Inthis application, we seek to study a novel pain mechanism in isolated human tissues. If positive results areobtained, we may have discovered a novel target to develop new anlagesics for treating women in pain.PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page)Project/Performance Site Primary LocationOrganizational Name:DUNS:Street 1: Street 2:City: County: State:Province: Country: Zip/Postal Code:Project/Performance Site Congressional Districts:Additional Project/Performance Site LocationOrganizational Name:DUNS:Street 1: Street 2:City: County: State:Province: Country: Zip/Postal Code:Project/Performance Site Congressional Districts:PHS 398 (Rev. 08/12 Approved Through 8/31/2015) OMB No. 0925-0001 Page 2 Form Page 2