Spinal mediators of nociceptive neurotransmission and hyperalgesia. Relationships among synaptic plasticity, analgesic tolerance, and blood flow

The synaptic mechanisms of nociception, hyperalgesia, allodynia, opioid tolerance, and neuropathic pain in the spinal cord dorsal horn are explored. The characteristics of the transmitters conveying excitation and the mechanisms that can enhance synaptic efficacy in the spinal nociceptive system after prolonged stimulation are examined, and a possible sequence of events that could contribute to progressive development, after intense or pathologic stimulation, of enhanced neuronal responsiveness from initial synaptic plasticity and hyperalgesia to subsequent neurotoxicity and neuropathic pain is described. The progression includes neurokinins and excitatory amino acids as neurotransmitters acting at neurokinins and excitatory amino acids receptors and evoking the production of nitric oxide by spinal interneurons. Finally, the importance of spinal blood flow as an affected function and an effective participant is discussed.