The M₂-Muscarinic Receptor Inhibits the Development of Streptozotocin-Induced Neuropathy in Mouse Urinary Bladder

Abstract

We investigate the role of M 2 -muscarinic receptors in maintaining neurogenic bladder contraction during hyperglycemia. Mice were injected with a single dose of streptozotocin (125 mg/kg), and neurogenic contraction of urinary bladder from wild type and M 2 -muscarinic receptor knockout (M 2 KO) mice was measured at 8 to 24 weeks after treatment. In wild-type bladder lacking urothelium, the summation of the cholinergic (64%) and purinergic (56%) components of the electrical-field-stimulated response exceeded 100%, indicating a reserve capacity. Although the cholinergic component was slightly less in the M 2 KO mouse, the total electrical-field-stimulated contraction was the same as wild type. The cholinergic and purinergic components of contraction in wild-type bladder were minimally affected by streptozotocin treatment. In M 2 KO bladder, streptozotocin treatment reduced both the cholinergic (after 8 -9 and 20 -24 weeks) and purinergic (after 20 -24 weeks only) components. The loss of function was approximately 50 to 70%. Similar results were observed in bladder with intact urothelium. M 2 KO bladder was more sensitive to the relaxant effect of isoproterenol compared with wild type, and this difference significantly increased at the early and late time points after streptozotocin treatment. In the presence of urothelium, however, this difference in isoproterenol sensitivity was smaller with streptozotocin treatment, but this trend reversed over time. Our results show that M 2 receptors oppose urinary bladder distension in wild-type bladder and inhibit streptozotocin-induced neuropathy.

Functional and Molecular Changes of the Bladder in Rats with Crushing Injury of Nerve Bundles from Major Pelvic Ganglion to the Bladder: Role of RhoA/Rho Kinase Pathway

“…From this result, we conclude that the M2 muscarinic receptors plays a more important role than the M3 muscarinic receptors after crushing nerve injury, and the role of the M2 or M3 receptor after nerve injury could be different from that of a normal bladder. Consistent with the results from the present study, several studies also have demonstrated that the M2 muscarinic receptors showed the more important role in denervated or hypertrophied bladder contraction [19,20]. Similar with the previous results, M2 muscarinic receptor expression after crushing injury was significantly increased compared with control or sham-operated groups, and this increased expression might be because of compensatory action to maintain bladder contraction.…”

“…A lower midline incision was made and the prostate gland was exposed. After identifying of MPG on the lateral side to bilateral prostates [20], the nerve bundles from the MPG to the bladder were identified and isolated (Figure 6). In sham-operated group, there was no further surgical manipulation.…”

A systematic review of urinary bladder hypertrophy in experimental diabetes: Part 2. Comparison of animal models and functional consequences

“…Finally, one of these studies suggested that enhancements may not be detectable at early time points (2 weeks after STZ injection) but only at later ones (8‐9 or 22‐24 weeks), which contrasts the time course of hypertrophy development; moreover, enhancements disappeared when contractions were normalized to those elicited by KCl, but interpretation of this finding is difficult as the KCl responses were not reported . A second report based on the same animals described a reduced contraction to EFS in M 2 receptor knock‐out but not wild‐type mice, which similarly involved the muscarinic and the purinergic component of contraction, pointing to possible compensatory changes in the contributions of M 2 and M 3 receptors.…”

Purinergic signalling and diabetes

“…Later, it was claimed that there was a reduction in the non-cholinergic contractile component of parasympathetic nerve stimulation in 12 weeks STZ-rats, probably caused by a reduction in release of the non-cholinergic transmitter [180]. It was proposed that cholinergic and purinergic parasympathetic nerve components of contraction were minimally affected by STZ treatment, but in M 2 -muscarinic knockout mouse bladder, STZ treatment reduced both the cholinergic and purinergic components [181]. There are conflicting reports about the changes in ATP-mediated neural responses in STZ-diabetic bladder.…”