A back-translational study of descending interactions with central mechanisms of hyperalgesia induced by high frequency stimulation in rat and human

In humans and animals, high frequency electrocutaneous stimulation (HFS) may produce an early long-term potentiation-like sensitisation. Peripheral and central modulatory processes are proposed to play a role. To explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we concurrently applied HFS with i) a conditioned pain modulation (CPM) paradigm during psychophysical testing in humans, or ii) a diffuse noxious inhibitory controls (DNIC) paradigm during in vivo electrophysiological recording of spinal neurones in anaesthetised animals in parallel studies that utilised identical stimuli. HFS induced enhanced perceptual responses to pin-prick stimuli in cutaneous areas secondary to the area of stimulation in humans and heightened the excitability of spinal neurones in rats (which exhibited stimulus intensity dependent coded responses to pin-prick stimulation in a manner that tracked with human psychophysics), where we also observed indicators of increased central neuronal hyperexcitability. In humans, a HFS(+CPM) paradigm did not alter primary or secondary hyperalgesia, and the area and pain intensity of secondary hyperalgesia did not correlate with temporal summation of pain or CPM magnitude, while in rats application of a DNIC paradigm concurrent to HFS did not impact the development of neuronal hyperexcitability. Concordance between human and rat data supports their translational validity. Our finding that excitatory signalling exceeds inhibitory controls suggests that dampening facilitatory mechanisms may be a preferable strategy for certain chronic pain states. If facilitatory mechanisms dominate, our data could explain why enhancing activity in descending inhibitory controls is not sufficient to induce pain relief in vulnerable patients. ### Competing Interest Statement The authors have declared no competing interest.