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NEUROPHARMACOLOGY

ATP Augments Peptide Release from Rat Sensory Neurons in Culture through Activation of P2Y Receptors

Department of Pharmacology and Toxicology (H.H., X.W.,G.D.N., M.R.V.) and Department of Anesthesia (M.R.V.), Indiana University School of Medicine, Indianapolis, Indiana; and Health Sciences Institute, The Procter and Gamble Company, Mason, Ohio (S.M.)

ATP has recently emerged as an important proinflammatory mediator that has direct excitatory actions on sensory neurons through activation of ion channel-coupled P2X receptors. The purpose of the current work is to assess whether ATP alters the release of neuropeptides from sensory neurons and the receptors mediating this putative action. Exposing embryonic sensory neurons in culture to concentrations of ATP up to 300 µM did not increase the release of immunoreactive substance P or calcitonin gene-related peptide from sensory neurons. However, pre-exposing sensory neurons to 0.1 to100 µM ATP prior to and throughout administration of 30 nM capsaicin resulted in a significant augmentation of release evoked by the vanilloid. This sensitizing action of ATP is blocked by suramin but not pyridoxal phosphate-6-azobenzene-2,4-disulfonic acid and is mimicked by the P2Y receptor agonists, 2-2-chloroadenosine triphosphate and UTP, but not by 2-(methylthio)adenosine 5'-triphosphate or ,-methyleneadenosine 5'-diphosphate. This profile of drug actions suggests that the sensitizing actions of ATP are mediated by P2Y receptors. Pretreating sensory neurons with bisindolylmaleimide I, a selective protein kinase C (PKC) inhibitor, attenuates the augmentation of capsaicin-induced peptide release by ATP, further implicating P2Y receptors in the actions of ATP. Immunoblotting also indicates the presence of P2Y₂-like immunoreactive substance in embryonic dorsal root ganglia neurons. Together, these data support the notion that ATP acts at P2Y receptors in sensory neurons in a PKC-dependent manner to augment their sensitivity to other stimuli.

Address correspondence to: Dr. Michael R. Vasko, Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5120. E-mail: vaskom{at}iupui.edu

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