Functional characterisation of a novel system for pain signalling in humans

Abstract

To protect the body from tissue damage, a quick evasive response is essential. The existence of fast and slow pain has long been accepted, with the slow pain having a burning quality and the fast pain having a sharp/pinprick quality. Slow-conducting C fibres are known to convey slow, or second, pain, while faster Aδ fibres signal fast, or first, pain. Although the body has afferents that conduct faster than Aδ fibres, these have not been associated with pain sensations. In light of the discovery of very fast-conducting fibres with a high mechanical threshold (Aβ high-threshold mechanoreceptors, or Aβ HTMRs), we aimed to investigate the large-fibre contribution to pain sensations in humans. We used the Nociceptive Withdrawal Reflex (NWR), known to reflect spinal nociceptive processing, as our experimental tool to test whether Aβ fibres contribute to nocifensive behaviour and pain sensation in humans. In Chapter/Paper I, we showed that the NWR did not primarily consist of two distinct latency components, and responses in the short-latency range were equally painful as long-latency responses. In Chapter/Paper II, the NWR was completely abolished when Aβ fibers were preferentially blocked by nerve ischemia, and electrical pain sensation at low stimulus intensities was significantly reduced. In Chapter III (manuscript), we elicited the Nociceptive Withdrawal Reflex using pinprick indentation, a stimulus preferred by mechano-nociceptors, including Aβ HTMRs. The mechanically evoked reflex was abolished when Aβ fibres were preferentially blocked, along with a reduction in mechanical pain at lower stimulus intensities. The reflex was further tested in a rare individual with Aβ deafferentation who had lost all touch sensation but could detect temperature. In this case, the NWR could not be evoked, and although mechanical pain could be evoked, the threshold was higher. Additionally, we tested the reflex in an individual with a rare gene mutation (FAAH-OUT), who does not perceive pain, and found that the reflex was preserved. In Chapter IV, we elicited the NWR using hair pulling, based on findings from parallel studies showing that a subtype of Aβ-HTMRs is selectively tuned to hair-pull stimuli. Hair pulling from the forearm resulted in short-latency reflex responses that were all perceived as painful. Collectively, these findings highlight the important role of Aβ fibres in nocifensive behaviour and pain perception. The newly discovered Aβ-HTMRs seem well-suited for this function.

Date of Thesis submission	2024
Original language	English
Awarding Institution	Western Sydney University
Sponsors	Australian Government Research Training Program Scholarship
Supervisor	Saad Nagi (Supervisor), David Mahns (Supervisor) & Håkan Olausson (Supervisor)