In a murine model of IC/PBS that recapitulates pelvic specific pain, we find that pelvic pain can be modulated by the neural-immune axis through blocking the actions of histamine or substance P. Previously, we showed that PRV-induced pelvic pain is mediated by mast cells via H1R and H2R, using both genetic and pharmacologic approaches [12
]. We expanded these observations in this study by demonstrating that both famotidine and cimetidine can attenuate pelvic pain similar to ranitidine, however ranitidine is the most effective, reducing 77% of the pelvic pain (Table ). We also find that the substance P receptor antagonist, L-703,606, attenuated pelvic pain by 77% demonstrating it to be as effective a ranitidine (Table ). Furthermore blocking H1R with diphenhydramine and cetirizine reduced pelvic pain by at least 40%, whereas the old generation H1R antagonist hydroxyzine had only a modest reduction in pelvic pain (Table ). In contrast to our previous study, however, diphenydramine pain blockade failed to achieve statistical robustness here (P < 0.08) due to unusual variability. One possible influence is unforeseen environmental factors, as the animal containment facilities necessary for PRV studies have relocated to a new building. Nonetheless, while these results emphasize the statistical vagaries inherent in small animal sample sizes, the findings here are consistent with our previous report. Conversely, proton pump inhibitors, histamine receptor 3 agonist, and gabapentin had little or no effect on PRV-induced pelvic pain (Table ). These data identify histamine 1 and 2 receptors and neurokinin 1 receptor as therapeutic targets for direct intervention in pelvic pain of IC/PBS.
Our data support a model of IC/PBS pathogenesis involving a positive feedback loop as originally postulated by Theoharides and Elbadawi, whereby substance P-containing peripheral nerves stimulate mast cells, in turn releasing histamine that induces pain originating from the bladder [6
]. Furthermore, histamine release by mast cells feeds back onto peripheral nerves to cause sustained release of substance P in the periphery to prolong mast cell activation or in the spinal cord to prolong neuronal excitation. This model is consistent with murine neurogenic cystitis and a subset of IC/PBS patients [7
]. We find that the substance P receptor antagonist, L-703,606, attenuated pelvic pain behavior by 77% (Table ). L-703,606, could be acting in the periphery to block substance P induction of mast cell-derived histamine and subsequent activation of pain fibers. Alternatively, L-703,606 could be acting in the spinal cord to block neuron-derived substance P activation of dorsal horn neurons that mediate pain. Regardless of the mechanism, our data demonstrate that blocking substance P attenuates pelvic pain in murine neurogenic cystitis and is a novel therapeutic target for direct intervention in pelvic pain.
We previously observed isolectin B4-positive processes within the lamina propria, where mast cells accumulate in IC/PBS and our murine IC model [4
], suggesting that interactions between mast cell histamine and C fiber nociceptors mediate pelvic pain in this IC/PBS model. This is reminiscent of an esophagitis model where mast cell histamine stimulates C fiber activity via H1R, therefore it is possible that histamine may act on bladder sensory nerves in IC/PBS because histamine metabolites are increased in IC/PBS urine [9
]. This mechanism is similar to patients with irritable bowel syndrome where abdominal/pelvic pain is correlated with activated colonic mucosal mast cells in proximity to nerves, and colonic tissue extracts that contained elevated histamine that excited rat nociceptors [29
]. These findings support the idea that neural-immune interactions can mediate pain in multiple pelvic pain syndromes.
Our evidence for histamine-mediated pelvic pain provides a mechanistic understanding of previous clinical findings. The H2R antagonist cimetidine produced significant improvement in pain and nocturia in a limited trial of IC/PBS patients [11
], however clinical trials have yet to be conducted with ranitidine or famotidine. Similarly, pilot clinical studies yielded modest pain relief in IC/PBS patients receiving the old-line H1R antagonist hydroxyzine (Atarax) [10
], but studies have not yet been conducted with newer generation H1R antagonists like diphenhydramine or cetirizine. Modern H1R antagonists likely attenuated pelvic pain better here than older generation H1R antagonists because newer H1R antagonists are well-absorbed, act faster, have greater efficacy, and a longer duration of action [30
]. We have previously shown that H1R and H2R are expressed in both the bladder and colon of mice, leaving the possibility of the H1R and H2R antihistamines acting at either or both of the organs to quell pelvic pain. Additionally, the colon modulates PRV-induced pelvic pain, pelvic organs generally exhibit neural-mediated crosstalk, and IBS is a co-morbidity of IC/PBS [13
]. Therefore, these epidemiologic and animal model findings together suggest that H1R and H2R antagonists may have general application for the treatment of pelvic pain.