The most common form of bladder pain in the clinic is that caused by infection, resulting in cystitis, although overdistension of the bladder in acute urinary retention is also very painful. These two mechanisms have been employed in the design of rodent models of bladder pain, using direct distension of the bladder, or instillation of chemical or infectious agents. Environmental stressors have also been used, as stress is known to exacerbate symptoms in human disease.
Ness et al. demonstrated reliable pressor and visceromotor responses during distension of the bladder in anesthetized rats that were inhibited dose-dependently by intravenous morphine or lidocaine (87). The authors did, in addition, point out that sex differences and estrous phase will alter the variability of results—something to consider during the experimental planning phase. Distension involves the catheterization of the bladder, either intrauretherally (females) or via a small abdominal incision (males); these two methods did not alter the results obtained (87). For the study of phasic distension, compressed air is blown into the bladder through the catheter until the required distension pressure is reached, and simultaneous recordings taken from surgically implanted electrodes in the abdominal muscle (for viscero-motor responses), and from cannulae in the jugular vein (heart rate) and carotid artery (blood pressure). Increasing the number of distensions performed was noted to increase the robustness of the recorded responses. Saline can be used in place of compressed air if a slow volume-controlled distension is required. Given the increasing interest in genetic manipulations of the mouse, this model has subsequently been characterized in mice, with similar results (88). As with the rat model, visceromotor responses were reproducible and attenuated by (subcutaneous) morphine; however, heart rate and respiratory responses may not be optimal pseudaffective responses with which to gauge the painful responses in this species.
The induction of cystitis, using the prodrug cyclophosphamide, is a common model of choice for assessing bladder hyper-reflexia and hypersensitivity; intraperitoneal cyclopho-sphamide administration results in the accumulation of its toxic metabolites (mostly acrolein) in the urine, which produce bladder irritation and inflammation. This model has the advantage that it does not require surgery, and appears to be similar to human visceral pain: cyclo-phosphamide-induced cystitis in humans is also painful. The behavioral effects of this model have been characterized in both rats (89) and mice (90) and show dose-related increases in pain-related behavior score (although the nature of the behaviors differed to a certain degree between species) that was reversed, again in a dose-dependent manner, by morphine. Rats and mice required one-time dosages of >100mgkg~ cyclophosphamide to produce an increase in behavioral score compared to controls, although this was not significantly so in mice; 300mgkg~1 was required (89,90). Administration of cyclophosphamide in lower, divided doses over the course of days produces bladder hypersensitivity with reduced bladder inflammation/hemorrhagic cystitis (Lamb and Gebhart, unpublished). It should also be noted that there is a significantly faster onset of behavioral score in female rats compared to their male counterparts, although both sexes plateau to the same value (91).
The direct intravesicular application of inflammatory agents such as acetic acid, acetone, capsaicin, croton oil, mustard oil, turpentine, and xylene has been employed as an alternative strategy to investigate bladder pain in rodents. McMahon and Abel (92) investigated the effects of turpentine (25%), mustard oil (2.5%), and croton oil (2%) instilled into the bladder via the urethra. They report a number of different observations that accompanied an inflammatory response: increased protein extravasation, bladder hyper-reflexia, and patterns of somatic pain behavior resembling referred visceral hyperalgesia, among others. The authors conclude by recommending the use of turpentine as the preferred agent. First demonstrated in decerebrate rats, this model has since been modified for use in anesthetized and unanes-thetized animals. Intravesicular instillation of xylene produces behavioral responses in the rat indicative of visceral pain (including evidence that the pain is referred to related somatic dermatomes) that are abolished following pelvic ganglionectomy and by prior administration of subcutaneous morphine (93,94). In this model, a narrow tube is chronically implanted into the bladder lumen under anesthesia and one end exteriorized to allow xylene administration (300 mL of 30%) 24 hours later.
Escherichia coli is the cause of the majority of urinary tract infections in humans, and intravesicular infusion of lipopolysaccharide from this bacteria, has been studied as a potential animal model of painful bladder inflammation. This, as with polyinosinic-polycytidylic acid
(a synthetic ribonucleic acid) or xylene, produces inflammation in the rat bladder for at least seven days and a concomitant decrease of substance P within the bladder (95). Since substance P is involved in nociception, and xylene produces behavioral responses consistent with the presentation of visceral pain, these models may also be considered relevant for use in pain research.
There also exist rodent models that employ environmental stress to instigate bladder pain. An example is the use of restraint stress, which results in the activation of three-quarters of bladder mast cells (96), but since such studies are yet to be validated in behavioral pain models, we shall not dwell upon them here. Note, however, that environmental stress likely affects many systems and can produce other visceral complications, such as those described above for the large intestine.
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