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ABSTRACT ObjectiveThis study aimed to investigate the potential role of cesium chloride (CsCl), ivabradine (IVA), and isoproterenol (ISO) on the sensory transmission of bladder afferents to graded urinary bladder distension (UBD). We specifically selected these drugs to target the hyperpolarization‐activated cyclic nucleotide‐gated (HCN) cation channels to determine their role in afferent encoding. MethodsThe bladders of C57BL/6 female mice were harvested with attached pelvic nerves in continuity, and the stimulus–response function (SRF) of bladder afferents to stepped bladder distension (20, 40, 60, 80 cmH2O) was recorded by single‐fiber recordings. Their changes in SRF to bath application of CsCl, IVA, and ISO were then evaluated. The presence of HCN on bladder afferent endings was assessed through immunohistological staining on bladder sections from mice with genetically labeled bladder afferents. ResultsIVA and ISO did not significantly reduce afferent responses to UBD, whereas CsCl increased afferent responses. Bladder afferents in the pelvic nerve pathway were categorized into low‐firing (LF, < 10 Hz) and high‐firing (HF, > 10 Hz) groups. SRF in both the LF and HF groups showed similar trends with no significant changes in response to IVA and ISO. CsCl increased SRF only in the HF group but not in the LF group. Immunohistological staining revealed that HCN1 does not extensively co‐localize with afferent endings, showing only sporadic presence. ConclusionOur targeted pharmacological studies with single‐fiber recordings and immunohistological staining collectively suggest that HCN channels do not play a significant role in bladder afferent sensory transmission.
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Blocking Aδ- and C-fiber neural transmission by sub-kilohertz peripheral nerve stimulation
IntroductionWe recently showed that sub-kilohertz electrical stimulation of the afferent somata in the dorsal root ganglia (DRG) reversibly blocks afferent transmission. Here, we further investigated whether similar conduction block can be achieved by stimulating the nerve trunk with electrical peripheral nerve stimulation (ePNS). MethodsWe explored the mechanisms and parameters of conduction block by ePNS via ex vivo single-fiber recordings from two somatic (sciatic and saphenous) and one autonomic (vagal) nerves harvested from mice. Action potentials were evoked on one end of the nerve and recorded on the other end from teased nerve filaments, i.e., single-fiber recordings. ePNS was delivered in the middle of the nerve trunk using a glass suction electrode at frequencies of 5, 10, 50, 100, 500, and 1000 Hz. ResultsSuprathreshold ePNS reversibly blocks axonal neural transmission of both thinly myelinated Aδ-fiber axons and unmyelinated C-fiber axons. ePNS leads to a progressive decrease in conduction velocity (CV) until transmission blockage, suggesting activity-dependent conduction slowing. The blocking efficiency is dependent on the axonal conduction velocity, with Aδ-fibers efficiently blocked by 50–1000 Hz stimulation and C-fibers blocked by 10–50 Hz. The corresponding NEURON simulation of action potential transmission indicates that the disrupted transmembrane sodium and potassium concentration gradients underly the transmission block by the ePNS. DiscussionThe current study provides direct evidence of reversible Aδ- and C-fiber transmission blockage by low-frequency (<100 Hz) electrical stimulation of the nerve trunk, a previously overlooked mechanism that can be harnessed to enhance the therapeutic effect of ePNS in treating neurological disorders.
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- Award ID(s):
- 1844762
- PAR ID:
- 10621893
- Publisher / Repository:
- Frontiers
- Date Published:
- Journal Name:
- Frontiers in Neuroscience
- Volume:
- 18
- ISSN:
- 1662-453X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fnins.2024.1404903
