Role of Mast Cells in Male Chronic Pelvic Pain

Abstract

Purpose Chronic pelvic pain syndrome (CPPS) accounts for 90% of all chronic prostatitis but has an unknown pathogenesis. In this study, we sought to understand the role of mast cells and nerve growth factor (NGF) in chronic pelvic pain. Materials and Methods Expressed prostatic secretions in men with CPPS and controls were tested for the presence of mast cell tryptase and NGF. Mast cell numbers, activation status and NGF expression were examined in the NOD/ShiLtJ experimental autoimmune prostatitis model (EAP) as well as in mast cell deficient KitW-sh/KitW-sh mice. Tactile allodynia was quantified using Von Frey filaments as a measure of pelvic pain behavior. Inhibitors of mast cell degranulation, histamine receptor antagonists and anti-NGF neutralizing antibodies were tested for reducing pelvic pain behavior. Results Men with CPPS demonstrated increased mast cell tryptase and NGF in expressed prostatic secretions. In the EAP model, increased total and activated mast cells were observed in the prostate. Mast cell deficient KitW-sh/KitW-sh mice showed attenuated pelvic pain behavior but no difference in inflammatory infiltrates in the prostate from controls. EAP mice also demonstrated increased intraprostatic NGF expression compared to KitW-sh/KitW-sh mice. Treatment of EAP with a mast cell stabilizer in combination with a histamine 1 receptor antagonist resulted in a synergistic reduction in chronic pelvic pain. In contrast, neutralization of NGF in vivo did not result in pain relief. Conclusions These results suggest that mast cells are important mediators of chronic pelvic pain in EAP and may be potential targets for therapeutic intervention in CP/CPPS.

Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation

“…As adults, the NMS mice display significant perigenital mechanical allodynia, as well as evidence of mast cell degranulation in prostate tissue. The use of NMS is a novel approach to developing a preclinical model of CP/CPPS in that it replicates the early life stress that is often reported by patients with chronic pelvic pain [12][13][14] , as well as incorporating a non-invasive induction, as opposed to more commonly used, chemically-and immunologically-induced inflammation of the prostate 34,[36][37][38][39] . Furthermore, NMS in mice has been shown to produce comorbid symptomology, including altered anxiety-like and anhedonic behaviors, increased micturition rates, and hindpaw hypersensitivity ( 16 ; data not shown), similar to the comorbid somatic, mood, and visceral disorders exhibited by CP/CPPS patients [4][5][6] .…”

“…Patients with CP/CPPS report pain in the perineum, rectum, prostate, penis, testicles, and/or abdomen 28 , experience a higher degree of psychological stress than control patients 29 , and commonly present with symptoms of or are diagnosed with comorbid chronic pelvic pain or mood disorders 5,[29][30][31] . Recurrent infection, leaky epithelium, neurogenic inflammation, and autoimmunity have all been surmised as potential underlying causes of CP/CPPS 2,32,33 , as well as mast cell activation and degranulation 34 . Expressed prostatic secretions from men with CP/ CPPS had increased mast cell tryptase and nerve growth factor (NGF) levels .…”

“…Expressed prostatic secretions from men with CP/ CPPS had increased mast cell tryptase and nerve growth factor (NGF) levels . Mast cell infiltration and activation/degranulation has been shown to increase following induction of EAP 34,35,40 . Transgenic mice deficient in either mast cells 34 or the tryptase receptor PAR2 35 do not develop prostatic tactic sensitivity following EAP, unlike wildtype EAP mice.…”

“…Mast cell infiltration and activation/degranulation has been shown to increase following induction of EAP 34,35,40 . Transgenic mice deficient in either mast cells 34 or the tryptase receptor PAR2 35 do not develop prostatic tactic sensitivity following EAP, unlike wildtype EAP mice. While this preclinical model replicates many of the characteristics of human CP/CPPS, the induction protocol is not indicative of the human condition, which has a diverse etiology and often does not involve direct inflammation, infection, or injury of the prostate.…”

Inflammation and Chronic Pelvic Pain: A Biological Trigger for Depression in Women?

“…However, the juxtaposition of SP-positive nerve fibers and MCs [80] may play an important role in pelvic organ cross-sensitization by amplifying afferent signaling. In fact, MC pro-inflammatory mediators can affect not only injured zones, but also adjacent territories, creating a secondary, widespread hyperalgesia [81]. The contribution of MCs to colon-bladder cross organ-sensitization induced by application of a colon chemical irritant has been confirmed using the MC stabilizing agent and histamine H1 agonist ketotifen fumarate [82].…”