title: Cyclophosphamide-induced cystitis reduces ASIC channel but enhances TRPV1 receptor function in rat bladder sensory neurons.
abstract: Using patch-clamp techniques, we studied the plasticity of acid-sensing ion channels (ASIC) and transient receptor potential V1 (TRPV1) channel function in dorsal root ganglia (DRG) neurons retrogradely labeled from the bladder. Saline (control) or cyclophosphamide (CYP) was given intraperitoneally on days 1, 3, and 5. On day 6, lumbosacral (LS, L6-S2) or thoracolumbar (TL, T13-L2) DRG were removed and dissociated. Bladders and bladder DRG neurons from CYP-treated rats showed signs of inflammation (greater myeloperoxidase activity; lower intramuscular wall pH) and increased size (whole cell capacitance), respectively, compared with controls. Most bladder neurons (>90%) responded to protons and capsaicin. Protons produced multiphasic currents with distinct kinetics, whereas capsaicin always triggered a sustained response. The TRPV1 receptor antagonist A-425619 abolished capsaicin-triggered currents and raised the threshold of heat-activated currents. Prolonged exposure to an acidic environment (pH range: 7.2 to 6.6) inhibited proton-evoked currents, potentiated the capsaicin-evoked current, and reduced the threshold of heat-activated currents in LS and TL bladder neurons. CYP treatment reduced density but not kinetics of all current components triggered by pH 5. In contrast, CYP-treatment was associated with an increased current density in response to capsaicin in LS and TL bladder neurons. Correspondingly, heat triggered current at a significantly lower temperature in bladder neurons from CYP-treated rats compared with controls. These results reveal that cystitis differentially affects TRPV1- and ASIC-mediated currents in both bladder sensory pathways. Acidification of the bladder wall during inflammation may contribute to changes in nociceptive transmission mediated through the TRPV1 receptor, suggesting a role for TRPV1 in hypersensitivity associated with cystitis.
authors: Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.
authors: Khoa
authors: K
authors: Dang
authors: Klaus
authors: K
authors: Bielefeldt
authors: G F
authors: GF
authors: Gebhart
mesh_terms: D062565:Acid Sensing Ion Channels / Q000502:physiology*; D000818:Animals; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000502:physiology*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology*; D001743:Urinary Bladder / Q000294:innervation*
chemical_list: D062565:Acid Sensing Ion Channels; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D003520:Cyclophosphamide
keywords: ASIC; TRPV1 receptors; acid; bladder sensory neurons; capsaicin; cyclophosphamide; cystitis; pH; proton; visceral hypersensitivity; whole cell patch clamp
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