Involvement of metabotropic glutamate receptor 5 in pudendal inhibition of nociceptive bladder activity in cats

Abstract

Non-technical summary Lower urinary tract disorders including painful and overactive bladder conditions are very difficult to treat. Neuromodulation which is one of the successful therapies for lower urinary tract disorders, stimulates afferent nerves to modulate the neural pathway and achieve a therapeutic effect. We show that the metabotropic glutamate receptor 5 is activated in the central nervous system during pudendal neuromodulation. Understanding the neurotransmitter mechanisms involved in neuromodulation therapy may promote the development of new pharmacological treatments or improve the clinical outcome by combining neuromodulation with pharmacological therapy.Abstract This study used MTEP, a metabotropic glutamate receptor 5 (mGluR5) antagonist, to examine the role of mGluR5 in the neural control of the urinary bladder and in the inhibition of the micturition reflex by pudendal nerve stimulation (PNS). Experiments were conducted in 11 female cats under α-chloralose anaesthesia when the bladder was infused with either saline or 0.25% acetic acid (AA). AA irritated the bladder, induced bladder overactivity and significantly (P < 0.001) reduced bladder capacity to 14.9 ± 10.3% of the saline control capacity. MTEP (0.1-50 mg kg −1 , I.V.) significantly (P < 0.05) increased bladder capacity during saline distension but not during AA irritation. However, MTEP induced a transient inhibition of isovolumetric bladder contractions under both conditions. PNS (5 Hz), which was tested at the threshold (T) intensity for inducing a complete inhibition of isovolumetric bladder contractions and at an intensity of 3-4T, suppressed AA-induced bladder overactivity and significantly increased bladder capacity to 68.0 ± 31.3% at 1T (P < 0.05) and 98.5 ± 55.3% at 3-4T (P < 0.01) of the saline control capacity. MTEP dose dependently (0.1-50 mg kg −1 , I.V.) suppressed PNS inhibition of bladder overactivity at low intensity (1T) but not at high intensity (3-4T). During saline infusion PNS significantly (P < 0.05) increased bladder capacity to 167.7 ± 27.1% at 1T and 196.0 ± 37.4% at 3-4T. These inhibitory effects were not observed after MTEP (0.1-50 mg kg −1 , I.V.) which also increased bladder capacity. These results indicate that glutamic acid has a transmitter function in bladder and somato-bladder reflex mechanisms and raise the possibility that mGluR5 may be a target for pharmacological treatment of lower urinary tract disorders.

Neural pathways involved in sacral neuromodulation of reflex bladder activity in cats

“…The possible contribution of peripheral mechanisms to sacral neuromodulation was important to evaluate because stimulation of a sacral spinal nerve can directly activate motor axons to the EUS, or reflexively activate these axons or lumbar sympathetic efferent axons that can modulate reflex bladder activity (6,15,16). When sympathetic efferent pathways in the hypogastric nerves are activated, they directly inhibit bladder smooth muscle and suppress synaptic transmission in bladder parasympathetic ganglia (7-9).…”

“…Then, S1 DRT stimulation at 5 Hz and at different intensities (1/4, 1/2, 1, and 2T) was applied during repeated CMGs. This was followed by two control CMGs without stimulation and a series of repeated CMGs with S1 DRT stimulations at 1T intensity and at several frequencies (5,15,30 Hz). After testing S1 DRT stimulation, the same stimulation parameters were tested again on the S2 DRT.…”

“…Monophasic pulses (0.2-ms pulse width) generated by an electrical stimulator (S88, Grass Medical Instruments, Quincy, MA) were delivered in each cat via a pair of hook electrodes first to the sacral DRTs and then to the sacral VRTs in the order of S1, S2, and S3. Eight different frequencies (1,3,5,7,10,15,20,30 Hz) were tested on every root in a random order to determine the effect on isovolumetric bladder contractions. Stimulation intensity was at the threshold (T) for inducing either anal sphincter or toe twitching, which was determined at the beginning of each experiment.…”

“…We used a chloralose-anesthetized cat model with a closed urethral outlet so that changes in reflex bladder activity are not influenced indirectly by fluid flowing in the urethra. Because this model has been used recently to study the effects of pudendal and tibial neuromodulation (15,26), the experiments will facilitate comparisons between the three types of neuromodulation and may provide information that could be used to improve therapy by optimizing stimulation location or stimulation parameters. …”

“…Several mechanisms are possible to account for the effects of sacral neuromodulation on bladder function, including: 1) direct activation of motor axons innervating the external urethral sphincter (EUS), which increases urethral outlet resistance or increases EUS afferent firing that in turn modulates bladder sensory or motor pathways in the central nervous system (6,14); 2) direct activation of afferent projections to the spinal cord that in turn modulate central bladder sensory or motor pathways (4,5,13,15); and 3) direct activation of afferent projections to the spinal cord that evoke sympathetic or EUS reflexes that inhibit the bladder or close the urethral outlet, respectively (11,16,30,31).…”