title: ATP-sensitive potassium currents reduce the PGE2-mediated enhancement of excitability in adult rat sensory neurons.
abstract: Behavioral studies have shown that the hyperalgesia arising from inflammatory agents, such as prostaglandin E(2) (PGE(2)), can be antagonized by activators of the ATP-sensitive potassium current (K(ATP)). This observation raises questions as to whether this suppression results from a direct action on sensory neurons and what are the cellular mechanisms giving rise to this inhibition. We found that small to medium diameter sensory neurons isolated from the L4-6 DRGs expressed the mRNAs for Kir6.1, Kir6.2, and SUR1. In perforated-patch clamp recordings from acutely dissociated sensory neurons from the young adult rat, exposure to 300 microM diazoxide, a K(ATP) channel agonist, significantly hyperpolarized the resting membrane potential, reduced the number of action potentials evoked by a ramp of depolarizing current, and increased the amplitude of inward K(ATP) currents evoked by the voltage ramp. Similar results were obtained with the protonophore FCCP, which is known to reduce the levels of intracellular ATP and lead to the activation of K(ATP). Only a subpopulation of sensory neurons was sensitive to diazoxide whereas other neurons were unaffected. Treatment with 1 microM PGE(2) significantly enhanced the excitability of these small to medium diameter capsaicin-sensitive sensory neurons; this enhancement was reversed by subsequent exposure to diazoxide in a subpopulation of neurons. Similar to diazoxide, exposure to 8-Br-cyclic GMP antagonized the PGE(2)-induced increase in excitability. The effects of 8-Br-cyclic GMP could be reversed by exposure to glibenclamide, an antagonist of K(ATP) channels. As with diazoxide, only a subpopulation of sensory neurons were affected by 8-Br-cyclic GMP. These results demonstrate that activation of K(ATP) can reverse the sensitization produced by PGE(2) and may be an important means to modulate the enhanced excitability that results from inflammatory or injury conditions.
authors.affiliation: Department of Pharmacology and Toxicology, 635 Barnhill Drive, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Xian Xuan
authors.initials: XX
authors.lastname: Chi
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: G D
authors.initials: GD
authors.lastname: Nicol
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism* / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000494:pharmacology; D054086:KATP Channels; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D015232:Dinoprostone; D018836:Inflammation Mediators; D054086:KATP Channels; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577509:Abcc8 protein, rat; C092520:uK-ATP-1 potassium channel