THE ROLE OF NERVE GROWTH-FACTOR IN A MODEL OF VISCERAL INFLAMMATION

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 ex perimental inflammation is created in anaesthetized rats with an irrit ant chemical. Within 1 h, bladder reflexes, activated by the sensory i nnervation of this viscus, become exaggerated, mimicking the disorders seen in humans with chronic cystitis. The development of this hyper-r eflexia following experimental inflammation was quantified using the t echnique of repeated cystometrograms. By several measures, bladder ref lex excitability increased about three-fold after 5 h. Firstly, the st udy investigated whether inflammatory changes can be prevented by phar macological antagonism of nerve growth factor. A synthetic fusion prot ein was used, consisting of the extracellular domain of the high-affin ity nerve growth factor receptor, trkA, coupled to the Fc portion of a n immunoglobulin. Previous work has shown that this molecule can seque ster 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 sig nificantly, prevented the expected increases in reflex excitability of this organ. Pretreatment with a related fusion protein, capable of se questering the neurotrophin brain-derived neurotrophic factor and neur otrophin-4/5, but not nerve growth factor, was without effect. Similar ly, a control fusion molecule, without neurotrophin-sequestering capac ity; 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 in flammatory changes, by about 30-60%, depending on outcome measure. The nerve growth factor-sequestering protein had no significant effects o n bladder reflex excitability in the uninflamed state. It was also wit hout significant effect on capsaicin-induced contractions of the urina ry bladder. Administration of exogenous nerve growth factor into the l umen of the urinary bladders of normal anaesthetized rats produced a r apid and marked bladder hyper-reflexia similar to that seen with exper imental inflammation. These findings are consistent with other circums tantial evidence that nerve growth factor may interact with visceral s ensory systems. Together, the data strongly suggest that nerve growth factor produced in inflamed tissues is a critical mediator of the sens ory disorders associated with inflammation. (C) 1997 IBRO. Published b y Elsevier Science Ltd.