The Dual Role of the Nitric Oxide/cGMP Pathway in Spinal Nociception

摘要

Nitric oxide (NO) is an important mediator of various physiological functions including vasodilatation, platelet aggregation, apoptosis, and neu-rotransmission. A large body of evidence indicates that NO also participates in spinal nociceptive processing and in the development of central sensitiza-tion, which occurs upon persistent activation of nociceptors by peripheral tissue injury and inflammation. In the superficial dorsal horn of the spinal cord, the persistent activation increases glutamate release with subsequent activation of various receptors such as the N-methyl-D-aspartate (NMDA) receptor. An increase in intracellular calcium concentration stimulates the Ca~(2+)/calmodulin-dependent neuronal NO synthase (nNOS), which triggers NO synthesis from L-arginine (Meller and Gebhart 1993; Vetter et al. 2001). NO is a small, gaseous molecule that is able to diffuse from the neuron where it is produced to neighboring cells. Therefore, it may act as a retrograde messenger that diffuses from the postsynaptic neuron back to the presynapse, thereby increasing the release of excitatory neurotransmitters (Meller and Gebhart 1993). This hypothesis is supported by the finding that extracellular NO scavengers such as hemoglobin are able to reduce NMDA-induced hyperalgesia in rodents (Kitto et al. 1992). In contrast to these well-documented pronociceptive effects of NO, several reports suggest that NO also may have antinociceptive properties (Luo and Cizkova 2000).