Modulation of activity-dependent excitability changes in subclasses of primary afferent nociceptors

The predominant problem of pain patients is supra-threshold pain. Ongoing activity in subclasses of primary afferent nociceptors strongly affects these pain levels. Therefore, the modulation of activity-dependent excitability changes in corresponding nociceptors may be substantial for regulating pain at clinically relevant intensities. Accordingly, a predominant focus on pain thresholds could have contributed to a translational gap in pain research so far. Therefore, we developed techniques that allowed us to bypass these processes and examine nociceptive activity and pain at supra-threshold levels. We used calcium imaging to study biophysical characteristics of outgrown porcine neurites in a compartmentalized Campenot chamber and found that neurites cultured with NGF showed TTX-r action potential conduction, indicating a strong expression of the TTX-r sodium channel NaV1.8. Furthermore, calcium influx in these neurites was substantially increased, which could be relevant in processes that facilitate post-excitatory neuronal excitability during repetitive firing. In analogy to these cultured neurites, our single fiber recordings also demonstrated TTX-r conduction in porcine silent nociceptors, indicating functional similarities between these fibers.
Additionally, we used a low-intensity electrical transcutaneous sinusoidal stimulus that preferentially activated C-fibers in human and animal skin. Interestingly, ongoing 4 Hz sinusoidal stimulation showed pain accommodation in healthy volunteers, but evoked increasing pain ratings in neuropathic pain patients. We also found that NaV1.8 is particularly important for 4 Hz sinusoidal activation, suggesting that NaV1.8 expressing silent nociceptors could play a significant role in this process.
These results and methods will add to the general understanding of nociceptive sensitization leading to ongoing pain.