Mast Cell-Derived Histamine Mediates Cystitis Pain

Abstract

BackgroundMast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC.Methods and FindingsInfection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology.ConclusionsThese data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions.

Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

“…The EvF protocol can easily be modified for use on tissues other than the hind paw e.g. abdomen 7 and ano-genital ridge 8 where CvF is currently used. Rodent models of allergies, wound healing, neuropathies and other pathologies can be easily adapted to include measures of mechanical sensitivity in tissues including and beyond the hind paw.…”

“…Place absorbent material below the stand to absorb/collect excreted waste. Allow mice to acclimate for 15 min in chambers prior to baseline or experimental withdrawal threshold assessment 6,7,10 . 5.…”

“…Reduction in time and intensity of previously specified responses to noxious stimuli are used to measure pain states in these animals as rodent subjects are not otherwise able to report a sensation of pain 6 . Altered responses to temperature and pressure are commonly used as metrics of tissue sensitivity in rodent models of inflammatory nociception that can be caused by infection 7,8 , chemical exposure 6,9,10 , surgical incision 11 , as well as neuropathic pain caused by nerve ligation 12 …”

The role of histamine in neurogenic inflammation

“…In fact, pain responses mediated by histamine and histamine receptors have been described in both animal and human models (Thilagarajah et al, 2001;Mobarakeh et al, 2006). Although the specific cell type (it could be mast cells, basophils, neutrophils or dendritic cells) or histaminergic neurons regulating histamine-mediated pain have not been identified, it has been demonstrated, using a model of PRV-induced pelvic pain in mast cell-deficient Kit W-sh /Kit W-sh mice, that mast cells are required for histamine-mediated pelvic pain (Rudick et al, 2008). However, the same authors demonstrated that Kit W-sh /Kit W-sh mice reconstituted with HDC -/-bone marrow exhibited diminished pain, thus suggesting that non-mast cell sources of histamine may also contribute to this pain response.…”

“…However, the same authors demonstrated that Kit W-sh /Kit W-sh mice reconstituted with HDC -/-bone marrow exhibited diminished pain, thus suggesting that non-mast cell sources of histamine may also contribute to this pain response. Moreover, Rudick et al (2008) demonstrated that PRV-induced pelvic pain is not dependent on TNF-mediated effects but is mediated by mast cell hista- mine, which then induces pain by stimulating histamine H1 and H2 receptors. Thus, it has been suggested that antagonists of histamine H1 and H2 receptors are suitable candidates in clinical trials for the treatment of chronic pain conditions, such as IC-related pelvic pain.…”