Pain receptors, also called nociceptors, are a group of sensory neurons with specialized nerve endings widely distributed in the skin, deep tissues (including the muscles and joints), and most of visceral organs. They respond to tissue injury or potentially damaging stimuli by sending nerve signals to the spinal cord and brain to begin the process of pain sensation. Nociceptors are equipped with specific molecular sensors, which detect extreme heat or cold and certain harmful chemicals. Mechanical nociceptors can also respond to tissue-damaging stimuli, such as pinching the skin or over-stretching the muscles. Activation of nociceptors generates action potentials, which are propagated along the afferent nerve axons, especially unmyelinated C-fibers and thinly myelinated Aδ-fibers. At the spinal cord level, the nociceptive nerve terminals release excitatory neurotransmitters to activate their respective postsynaptic receptors on second-order neurons. In the spinal dorsal horn, both excitatory and inhibitory interneurons can augment or attenuate nociceptive transmission (Cervero & Iggo, 1980; Zhou, Zhang, Chen, & Pan, 2007, 2008). The nociceptive signal, encoding the quality, location, and intensity of the noxious stimuli, is then conveyed via the ascending pathway to reach various brain regions to elicit pain sensation. Physiological pain responses normally protect us from tissue damage by quickly alerting us to impending injury. Unlike acute physiological pain, chronic pathological pain, including neuropathic and inflammatory pain, is often associated with increased activity and responses of spinal dorsal horn neurons, termed central sensitization (Woolf & Thompson, 1991; Xu, Dalsgaard, & Wiesenfeld-Hallin, 1992). This phenomenon is the cellular basis for hyperalgesia (increased pain response to a noxious stimulus) and allodynia (painful sensation in response to a nonnoxious stimulus).
Nitric oxide (NO) is a membrane-permeable gaseous second messenger involved in signal transduction. The physiological function of NO has been shown in a large variety of cell types and tissues, including the immune system, blood vessels, endothelial cells, and neurons. NO is produced from l-arginine by three major isoforms of nitric oxide synthase (NOS): neuronal NOS (nNOS or NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3) (Alderton, Cooper, & Knowles, 2001; Knowles & Moncada, 1994). Both nNOS and eNOS are constitutively expressed and activated by Ca2 +/calmoduline-dependent signaling, whereas iNOS is typically induced by immunostimulation, such as inflammatory cytokines and bacterial endotoxins, independent of intracellular Ca2 + levels. Classically, the intracellular NO effect is mediated by the NO-sensitive soluble guanylyl cyclase (sGC). When activated, sGC converts guanosine triphosphates (GTP) into cyclic guanosine monophosphates (cGMP). cGMP has different targets such as serine/threonine protein kinases G (PKG-I and PKG-II), cGMP-regulated phosphodiesterase, and cGMP-activated ion channels (Ahern, Klyachko, & Jackson, 2002; Calabrese et al., 2007). In addition, NO can promote a covalent and reversible posttranslational protein modification by interacting with the thiol side chain of cysteine residues. This chemical reaction, named S-nitrosylation, occurs without the action of any enzymes (Ahern et al., 2002; Choi et al., 2000).
The role of NO in pain signaling has been investigated in many studies using rodent models and in humans. In this chapter, we critically review the reported complex actions of NO in pain transduction and transmission. We also present recent electrophysiological evidence showing that NO inhibits nociceptive transmission at the spinal cord level and the signaling mechanisms involved.