Selective ablation of spinal neurons possessing substance P receptors (NK-1 receptors) using the selective cytotoxin conjugate substance P-saporin (SP-SAP) decreases hyperalgesia and central sensitization. The mechanisms by which NK-1 expressing neurons modulate the excitability of other dorsal horn neurons are unclear. Because the majority of NK-1 expressing spinal neurons project rostrally, it is possible that they are part of a spinal-supraspinal circuitry that contributes to descending modulation of excitability of spinal nociceptive neurons. We therefore determined whether ablation of spinal neurons that possess the NK-1 receptor altered descending systems that travel via the dorsolateral funiculus (DLF). Spontaneous activity and responses of dorsal horn neurons evoked by mechanical (von Frey monofilaments) and heat (35-51 °C) stimuli were determined before and after transection of the DLF and were compared in rats pretreated with intrathecal application of vehicle or SP-SAP. In vehicle-treated rats, transection of the DLF caused a 233% increase in mean spontaneous activity of neurons and enhanced their responses to mechanical and heat stimuli, whereas these increases in excitation were blocked in rats pretreated with SP-SAP. Importantly, SP-SAP alone had no effect on spontaneous or evoked activity in the absence of DLF transection. These results demonstrate that spinal neurons expressing the NK-1 receptor appear to play a pivotal role in regulating descending systems that modulate activity of nociceptive dorsal horn neurons.
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