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The Journal of Neuroscience, December 15, 1998, 18(24):10375-10388

Nitric Oxide-Producing Islet Cells Modulate the Release of Sensory Neuropeptides in the Rat Substantia Gelatinosa

Patrizia Aimar¹, Lucia Pasti², Giorgio Carmignoto², and Adalberto Merighi¹

¹ Dipartimento di Morfofisiologia Veterinaria, Università degli Studi di Torino, I-10126 Torino, Italy, and ² Dipartimento di Scienze Biomediche Sperimentali, Università degli Studi di Padova, I-3531, and Centro per lo Studio delle Biomembrane del Consiglio Nazionale delle Ricerche, Padova, Italy, European Union

The substantia gelatinosa of the spinal cord (lamina II) is the major site of integration for nociceptive information. Activation of NMDA glutamate receptor, production of nitric oxide (NO), and enhanced release of substance P and calcitonin gene-related peptide (CGRP) from primary afferents are key events in pain perception and central hyperexcitability. By combining reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry for NO-producing neurons with immunogold labeling for substance P, CGRP, and glutamate, we show that (1) NO-producing neurons in lamina II_i are islet cells; (2) these neurons rarely form synapses onto peptide-immunoreactive profiles; and (3) NADPH diaphorase-positive dendrites are often in close spatial relationship with peptide-containing terminals and are observed at the periphery of type II glomeruli showing glutamate-immunoreactive central endings. By means of confocal fluorescent microscopy in acute spinal cord slices loaded with the Ca²⁺ indicator Indo-1, we also demonstrate that (1) NMDA evokes a substantial [Ca²⁺]_i increase in a subpopulation of neurons in laminae I-II, with morphological features similar to those of islet cells; (2) a different neuronal population in laminae I-II_o, unresponsive to NMDA, displays a significant [Ca²⁺]_i increase after slice perfusion with either substance P and the NO donor 3morpholinosydnonimine (SIN-1); and (3) the responses to both substance P and SIN-1 are either abolished or significantly inhibited by the NK₁ receptor antagonist sendide. These results provide compelling evidence that glutamate released at type II glomeruli triggers the production of NO in islet cells within lamina II_i after NMDA receptor activation. The release of substance P from primary afferents triggered by newly synthesized NO may play a crucial role in the cellular mechanism leading to spinal hyperexcitability and increased pain perception.

Key words: CGRP; substance P; nitric oxide; pain; hyperalgesia; confocal microscopy; electron microscopy; NMDA receptor; calcium signaling; spinal cord slice

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182410375-14$05.00/0

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				W. Guo, H. Wang, M. Watanabe, K. Shimizu, S. Zou, S. C. LaGraize, F. Wei, R. Dubner, and K. Ren Glial-Cytokine-Neuronal Interactions Underlying the Mechanisms of Persistent Pain J. Neurosci., May 30, 2007; 27(22): 6006 - 6018. [Abstract] [Full Text] [PDF]

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