The Differences of Pain Receptor and Pain-Related Neurotransmitters in the Vagina of Pre- and Post- Menopausal Women

Objective: Post-menopausal vaginal pain and burning sensation are not solely relieved by improving vaginal dryness. Stimulation of pain receptor (nociceptor) may be a part of the post-menopausal vaginal pain mechanism. The authors primarily evaluated the level of substance P receptor in pre- and post-menopausal women and secondarily studied the level of calcitonin gene-related peptide (CGRP) receptor and nociceptor-activating substances in pre- and post-menopausal women. The association between vaginal pain score and the change in nociceptor and nociceptoractivating substances was analyzed. Materials and Methods: A cross-sectional study was conducted in 122 pre- and post-menopausal women that underwent total abdominal hysterectomy. Vaginal specimens were obtained and stained for substance P receptor, substance P, CGRP receptor and CGRP, which were used as nociceptive parameters in the present study. Vaginal stromal cells were counted for pain-related protein expressions. Mean pain-related protein expressions in vaginal stromal cells were compared between pre- and post-menopausal women. Results: Fifty-eight pre-menopausal women and 33 post-menopausal women were included for analysis. Mean substance P receptor, substance P, CGRP receptor and CGRP in post-menopausal women were higher than in pre-menopausal women (47.69, 42.32, 71.31 and 60.73 cells, respectively for post-menopausal women, and 22.03, 21.54, 41.45 and 35.80 cells, respectively for pre-menopausal women). These differences were under the major influence of hormonal status rather than age. The changes in mean pain-related protein expression in vaginal stromal cell after menopause were highest in the first two years. No difference in mean pain-related protein expression in vaginal stromal cell was observed between pain and no pain groups. Conclusion: In the present study, post-menopausal women were found to have higher mean pain-related protein expressions in vaginal stromal cells than pre-menopausal women. Keywords: Post-menopausal women, Vaginal pain, Vaginal dryness, Vaginal burning sensation, Vaginal nerve, Substance P, CGRP, Calcitonin gene-related peptide

Experimental Hypomagnesemia Induces Neurogenic Inflammation and Cardiac Dysfunction

Hypomagnesemia occurs clinically as a result of restricted dietary intake, Mg-wasting drug therapies, chronic disease status and may be a risk factor in patients with cardiovascular disorders. Dietary restriction of magnesium (Mg deficiency) in animal models produced a pro-inflammatory/pro-oxidant condition, involving hematopoietic, neuronal, cardiovascular, renal and other systems. In Mg-deficient rodents, early elevations in circulating levels of the neuropeptide, substance P (SP) may trigger subsequent deleterious inflammatory/oxidative/nitrosative stress events. Evidence also suggests that activity of neutral endopeptidase (NEP, neprilysin), the major SP-degrading enzyme, may be impaired during later stages of Mg deficiency, and this may sustain the neurogenic inflammatory response. In this article, experimental findings using substance P receptor blockade, NEP inhibition, and N-methyl-D-aspartate (NMDA) receptor blockade demonstrated the connection between hypomagnesemia, neurogenic inflammation, oxidative stress and enhanced cardiac dysfunction. Proof of concept concerning neurogenic inflammation is provided using an isolated perfused rat heart model exposed to acute reductions in perfusate magnesium concentrations.

Dipeptidyl Peptidase 4 Inhibition Increases Postprandial Norepinephrine via Substance P (NK1 Receptor) During RAAS Inhibition

Context Dipeptidyl peptidase 4 (DPP4) inhibitors may increase the risk of heart failure. Decreased degradation of vasoactive peptides like substance P [also degraded by angiotensin-converting enzyme (ACE)] and Y1 agonists peptide YY (PYY 1-36) and neuropeptide Y (NPY 1-36) could contribute. Objective This study tested the hypothesis that there is an interactive effect of DPP4 inhibition and ACE inhibition (vs antihypertensive control subjects) on vasoactive peptides after a mixed meal. Participants and Design Fifty-three patients with type 2 diabetes and hypertension were randomized to double-blind treatment with ramipril, valsartan, or amlodipine for 15 weeks in parallel groups. During the 5th, 10th, and 15th weeks, participants also received placebo + placebo, sitagliptin 100 mg/d + placebo, and sitagliptin + aprepitant 80 mg/d in random order. On the last day of each crossover treatment, participants underwent a mixed-meal study. Results Sitagliptin increased postprandial glucagon-like peptide-1 and decreased glucose in all antihypertensive groups. Sitagliptin increased NPY 1-36 and decreased Y2 agonists NPY 3-36 and PYY 3-36 in all groups. During ramipril or valsartan, but not amlodipine, sitagliptin increased postprandial norepinephrine; substance P receptor blockade with aprepitant prevented this effect. Despite increased norepinephrine, sitagliptin decreased postprandial blood pressure during ACE inhibition. Conclusion DPP4 inhibition increases postprandial concentrations of the Y1 agonist NPY 1-36. During treatment with an ACE inhibitor or angiotensin receptor blocker, DPP4 inhibition increased postprandial norepinephrine through a substance P receptor–dependent mechanism. Increased NPY 1-36 and norepinephrine could increase risk of heart failure but did not result in higher postprandial blood pressure.