Nerve growth factor mediates peripheral mechanical hypersensitivity that accompanies experimental cystitis in mice.
ABSTRACT Increased sensitivity to somatic stimuli has been noted in the presence of visceral inflammation. Cystitis was induced by intraperitoneal injection of cyclophosphamide (CYP) in female mice. Sensitivity of hind paws to mechanical stimuli was determined prior to and 4, 9 and 24 h after CYP, and sensitivity of the tail to thermal stimuli was determined prior to, 4 and 24 h after CYP treatment. To investigate the role of nerve growth factor (NGF) in these processes, other groups of mice received NGF antiserum, normal serum, or K252a intravenously 30 min after CYP administration. CYP induced bladder inflammation that was not ablated by treatment with NGF antiserum or K252a. Sensitivity to mechanical stimuli was increased 4 and 9 h after CYP administration. This was reversed by NGF antiserum or K252a but not by normal serum. After 24 h, no differences were observed in withdrawal threshold among groups. None of the treatments had any effect on sensitivity to thermal stimuli. To further investigate the role of NGF in this process, NGF was instilled into the bladders of mice in the presence or absence of intravenous NGF antiserum. Four hours after intravesical instillation of NGF, the threshold of the hind paws to mechanical stimulation was significantly decreased, and this effect was reversed by prior treatment with NGF antiserum. This model of visceral pain causes increased sensitivity to peripheral application of mechanical stimuli. This effect is at least partially mediated by NGF, and the bladder may be the source of NGF in this process.
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ABSTRACT: Mast 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. Infection 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. These 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.PLoS ONE 02/2008; 3(5):e2096. · 4.09 Impact Factor