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

Abstract

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 Aδ-fiber range consistent with the canonical view that “fast pain” is signaled by Aδ nociceptors. We recently demonstrated that human skin is equipped with ultrafast (Aβ 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 reflex responses in the presumed Aδ range were considered. 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 based on reflex latencies. We found that shorter latency reflexes were just as painful as those in the conventional latency range.ConclusionWe 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. Whether these are signaled by the ultrafast nociceptors remains to be determined.

Experimental nerve block study on painful withdrawal reflex responses in humans

“…The NWR responses in our data had latencies ranging from 65 to 137 ms, corresponding to a mix of RII and RIII latencies; however, they were equally painful. Based on the current and our previous findings (Thorell et al, 2023), it is evident that the NWR response does not always comprise a double EMG burst and can be just as painful regardless of reflex latency.…”

“…Ruscheweyh et al, 2011; Sandrini et al, 1993; Ydrefors et al, 2020). In our earlier work involving transcutaneous electrical stimulation, dual reflex responses (RII and RIII) were observed in 12% of reflex recordings (Thorell et al, 2023). In the current study using intradermal electrical stimulation, no instances of dual RII-RIII responses were observed (Fig.…”

“…1C). When applying a cut-off of 96 ms derived from the analysis of dual reflex responses (Thorell et al, 2023) to this dataset, 137 NWR responses (69.2%) had latencies under 96 ms. Importantly, reflex responses with short and long latencies were equally painful (Fig.…”

PIEZO2‐dependent rapid pain system in humans and mice

“…Importantly, the pain ratings increased with the pulling force, indicating that hair-pull pain was a scalable sensation (Figure 1G). Then, we used a progressive nerve ischemic block, induced by a blood pressure cuff 20 , to dissociate the contributions of different afferent fiber Latency distribution of reflex responses recorded in anterior and posterior muscle compartments of the upper arm and corresponding pain ratings. Since no differences were found in reflex latencies and pain ratings (p>0.05; t-test) between the two compartments, the data were pooled.…”

“…An ischemic block was applied to examine the contribution of different afferent fiber classes to the perception of single hair-pull pain. Briefly, a blood pressure cuff was wrapped around the upper arm or above the ankle of the participant and rapidly inflated to 300 mmHg 20 . Then, selective sensory stimuli were applied to gauge the progression of the nerve block, with vibration intensity and detection of cooling and warming taken as measures for Aβ-, Aδ-, and C-fiber function, respectively 21 .…”