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The Journal of Neuroscience, January 28, 2004, 24(4):797-807; doi:10.1523/JNEUROSCI.4019-03.2004

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Cellular/Molecular
Inhibition of N-Type Voltage-Activated Calcium Channels in Rat Dorsal Root Ganglion Neurons by P2Y Receptors Is a Possible Mechanism of ADP-Induced Analgesia

Zoltan Gerevich,¹ Sebestyen J. Borvendeg,¹ Wolfgang Schröder,² Heike Franke,¹ Kerstin Wirkner,¹ Wolfgang Nörenberg,¹ Susanna Fürst,⁴ Clemens Gillen,³ and Peter Illes¹

¹Rudolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, D-04107 Leipzig, Germany, Departments of ²Pharmacology and ³Molecular Pharmacology, Grünenthal GmbH, D-52099 Aachen, Germany, and ⁴Hungarian Academy of Sciences, Group of Neuropsychopharmacology, Department of Pharmacology and Pharmacotherapy, Semmelweis University, H-1445 Budapest, Hungary

Patch-clamp recordings from small-diameter rat dorsal root ganglion (DRG) neurons maintained in culture demonstrated preferential inhibition by ATP of high-voltage-activated, but not low-voltage-activated, Ca²⁺ currents (I_Ca). The rank order of agonist potency was UTP > ADP > ATP. ATP depressed the -conotoxin GVIA-sensitive N-type current only. Pyridoxal-5-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) and 2'-deoxy-N⁶-methyladenosine 3',5'-bisphosphate tetraammonium, two P2Y₁ receptor antagonists, almost abolished the ATP-induced inhibition. Both patch-clamp recordings and immunocytochemistry coupled with confocal laser microscopy indicated a colocalization of functional P2X₃ and P2Y₁ receptors on the same DRG neurons. Because the effect of ATP was inhibited by intracellular guanosine 5'-O-(2-thiodiphosphate) or by applying a strongly depolarizing prepulse, P2Y₁ receptors appear to block I_Ca by a pathway involving the subunit of a G_q/11 protein. Less efficient buffering of the intracellular Ca²⁺ concentration ([Ca²⁺]_i) by reducing the intrapipette EGTA failed to interfere with the ATP effect. Fura-2 microfluorimetry suggested that ATP raised [Ca²⁺]_i by a G-mediated release from intracellular pools and simultaneously depressed the high external potassium concentration-induced increase of [Ca²⁺]_i by inhibiting I_Ca via G. Adenosine 5'-O-(2-thiodiphosphate) inhibited dorsal root-evoked polysynaptic population EPSPs in the hemisected rat spinal cord and prolonged the nociceptive threshold on intrathecal application in the tail-flick assay. These effects were not antagonized by PPADS. Hence, P2Y receptor activation by ADP, which is generated by enzymatic degradation of ATP, may decrease the release of glutamate from DRG terminals in the spinal cord and thereby partly counterbalance the algogenic effect of ATP.

Key words: ATP; P2Y receptor; calcium channel; dorsal root ganglion; patch clamp; analgesia

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Received Sep 1, 2003; revised November 4, 2003; accepted November 6, 2003.

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