Elsevier

Neuroscience

Volume 78, Issue 2, 10 March 1997, Pages 449-459
Neuroscience

The role of nerve growth factor in a model of visceral inflammation

https://doi.org/10.1016/S0306-4522(96)00575-1Get rights and content

Abstract

There is growing evidence that nerve growth factor may be an important mediator of the sensory disorders associated with inflammation. This hypothesis was tested in a rat model of cystitis. In this model, an experimental inflammation is created in anaesthetized rats with an irritant chemical. Within 1 h, bladder reflexes, activated by the sensory innervation of this viscus, become exaggerated, mimicking the disorders seen in humans with chronic cystitis. The development of this hyper-reflexia following experimental inflammation was quantified using the technique of repeated cystometrograms. By several measures, bladder reflex excitability increased about three-fold after 5 h. Firstly, the study investigated whether inflammatory changes can be prevented by pharmacological antagonism of nerve growth factor. A synthetic fusion protein was used, consisting of the extracelluar domain of the high-affinity nerve growth factor receptor, trkA, coupled to the Fc portion of an immunoglobulin. Previous work has shown that this molecule can sequester nerve growth factor and reduce its bioavailability both in vitro and in vivo. Treatment of animals with the fusion molecule at 1 mg/kg, immediately before inflammation of the bladder, largely, and very significantly, prevented the expected increases in reflex excitability of this organ. Pretreatment with a related fusion protein, capable of sequestering neurotrophin brain-derived neurotrophic factor and neurotrophin-4/5, but not nerve growth factor, was without effect. Similarly, a control fusion molecule, without neurotrophin-sequestering capacity, did not reduce the inflammation-induced hyper-reflexia. Systemic treatment with the nerve growth factor-sequestering molecule, but not control molecules, partially and significantly reversed established inflammatory changes, by about 30–60%, depending on outcome measure. The nerve growth factor-sequestering protein had no significant effects on bladder reflex excitability in the uninflamed state. It was also without significant effect on capsaicin-induced contractions of the urinary bladder. Administration of exogenous nerve growth factor into the lumen of the urinary bladders of normal anaesthetized rats produced a rapid and marked bladder hyper-reflexia similar to that seen with experimental inflammation.

These findings are consistent with other circumstantial evidence that nerve growth factor may interact with visceral sensory systems. Together, the data strongly suggest that nerve growth factor produced in inflamed tissues is a critical mediator of the sensory disorders associated with inflammation.

Section snippets

Animal maintenance and surgery

This study was carried out on 59 female Wistar rats, weighing 225–260 g. The animals were anaesthetized with a single dose of urethane (1.25 g/kg, i.p.), which produced a stable level of anaesthesia lasting for the entire experiment. The trachea and one carotid artery were cannulated. Body temperature was measured and maintained close to 37°C. The bladder was catheterized transurethrally with a 1.1-mm polythene catheter. A ventral midline laparotomy was performed, enabling complete bladder

Results

The control cystometrograms in all treatment groups were similar. The average NC was low (3.1±0.3, n=59), as was the average TCT (157.3±13.8 s, n=59), while baseline MTs were moderately high (0.45±0.03 ml, n=59). Examples of representative cystometrograms are shown in Fig. 1, Fig. 5.

Discussion

In these experiments we set out to test the hypothesis that NGF functions as a mediator of sensory disorders associated with inflammation. A well-described model of cystitis in the rat was used.17, 18, 19, 33, 35Bladder reflex activity was studied, rather than, for instance, single afferent fibre activity, because it offers a robust measure of the integrated neuronal response to inflammation. Repeated measures can be made, allowing the time-course of effects to be conveniently studied. It is

Conclusions

Taken together, these findings suggest that our experimental observations may be relevant to some painful disorders of the urinary bladder in humans. The implication is that anti-NGF strategies may be of some therapeutic benefit in treating these clinical disorders.

Acknowledgements

This work was supported by a grant from the MRC of Great Britain. ND is supported by a studentship from CONICIT. We would also like to thank Caroline Abel, Tabitha Springhall and Sridhar Viswanathan for excellent technical help, and Paul Seed for statistical advice.

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