Biology subjects

Thorell, O.

Publications and source records attributed to Thorell, O..

3 recordsLinked to original sources

bioRxiv2023

PIEZO2-dependent rapid pain system in humans and mice.

The PIEZO2 ion channel is critical for transducing light touch into neural signals but is not considered necessary for transducing acute pain in humans. Here, we discovered an exception - a form of mechanical pain evoked by hair pulling. Based on observations in a rare group of individuals with PIEZO2 deficiency syndrome, we demonstrated that hair-pull pain is dependent on PIEZO2 transduction. Studies in control participants showed that hair-pull pain triggered a distinct nocifensive response, including a nociceptive reflex. Observations in rare A{beta} deafferented individuals and nerve conduction block studies in control participants revealed that hair-pull pain perception is dependent on A{beta} input. Single-unit axonal recordings revealed that a class of cooling-responsive myelinated nociceptors in human skin is selectively tuned to painful hair-pull stimuli. Further, we pharmacologically mapped these nociceptors to a specific transcriptomic class. Finally, using functional imaging in mice, we demonstrated that in a homologous nociceptor, Piezo2 is necessary for high-sensitivity, robust activation by hair-pull stimuli. Together, we have demonstrated that hair-pulling evokes a distinct type of pain with conserved behavioral, neural, and molecular features across humans and mice.

neuroscience↗

bioRxiv2023

The role of cutaneous Aβ fibers in human nocifensive functions: Nerve block study on painful withdrawal reflex responses

The nociceptive withdrawal reflex (NWR) is a protective limb withdrawal response triggered by painful stimuli, used to assess spinal nociceptive excitability. Conventionally, the NWR is understood as having two reflex responses: a short-latency A{beta}-mediated response, considered tactile, and a longer-latency A{delta}-mediated response, considered nociceptive. However, nociceptors with conduction velocities similar to A{beta} tactile afferents have been identified in human skin. In this study, we investigated the effect of a preferential conduction block of A{beta} fibers on pain perception and NWR signaling evoked by intradermal electrical stimulation in healthy participants. We recorded a total of 198 NWR responses in the intact condition, and no dual reflex responses occurred within our latency bandwidth (50-150 ms). The current intensity required to evoke the NWR was magnitude higher than the perceptual pain threshold, indicating that NWR did not occur before pain was felt. In the block condition, when the A{beta}-mediated tuning fork sensation was lost while A{delta}-mediated nonpainful cooling was still detectable (albeit reduced), we observed that the reflex was abolished. Further, short-latency electrical pain intensity at pre-block thresholds was greatly reduced, with any residual pain sensation having a longer latency. Although electrical pain was unaffected at suprathreshold current intensities, the reflex could not be evoked despite a two-fold increase in the pre-block current intensity and a five-fold increase in the pre-block pulse duration. These observations lend support to the possible involvement of A{beta}-fiber inputs in pain and reflex signaling.

neuroscience↗

bioRxiv2022

Investigations into an overlooked early component of painful nociceptive withdrawal reflex responses in humans

IntroductionThe role of pain as a warning system necessitates a rapid transmission of information from the periphery for the execution of appropriate motor responses. The nociceptive withdrawal reflex (NWR) is a physiological response to protect the limb from a painful stimulus and is often considered an objective measure of spinal nociceptive excitability. The NWR is commonly defined by its latency in the presumed Ad-fiber range consistent with the canonical view that "fast pain" is signaled by Ad nociceptors. We recently demonstrated that human skin is equipped with ultrafast (A{beta} range) nociceptors. Here, we investigated the short-latency component of the reflex and explored the relationship between reflex latency and pain perception. MethodsWe revisited our earlier work on NWR measurements in which, following convention, only those reflex responses were selected that were in the presumed Ad range (taken to be latencies [≥]90 ms in that study). In our current analysis, we expanded the time window to search for shorter latency responses and compared those with pain ratings. ResultsIn both cohorts, we found an abundance of recordings with short-latency reflex responses. In nearly 90% of successful recordings, only single reflex responses (not dual) were seen which allowed us to compare pain ratings to reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range. DiscussionWe found a preponderance of short-latency painful reflex responses. Based on this finding, we suggest that short-latency responses must be considered in future studies. We predict these might be signaled by the ultrafast nociceptors, warranting further investigation.

neuroscience↗