There is considerable evidence to implicate N-methyl-D-aspartate (NMDA) receptor activation in the mechanisms that underly thermal hyperalgesia in the spinal cord. As many of the effects of NMDA receptor activation appear to be ultimately mediated through production of nitric oxide (NO), recent reports have begun to define the role of NO in spinal nociceptive processing. From this evidence, it is likely that NO, produced in neurons in the spinal cord that contain NO synthase, like NMDA, plays a pivotal role in multisynaptic local circuit nociceptive processing in the spinal cord. Collectively, these reports suggest that the reflex withdrawal response to noxious heat is not mediated through activation of NMDA receptors and subsequent production of NO and cGMP, but that the acute NMDA-produced facilitation of thermal reflexes is NMDA-, NO- and cGMP-mediated and that a sustained production of NO and subsequent activation of soluble guanylate cyclase (GC-S) in the lumbar spinal cord appears to be required for maintenance of the thermal hyperalgesia produced in persistent pain models. As our knowledge and understanding of the new and intriguing class of neurotransmitters typified by NO emerges, it is likely that the next few years of pain and analgesia research will focus on the cellular events underlying mechanisms of chronic pain.