Within the brain, complex neurocircuitry integrates an array of signals to regulate postganglionic sympathetic neural discharge patterns. Recently, there has been increased interest in understanding the complexities of the central neural determinants of muscle sympathetic nerve activity (MSNA) in humans (Macefield & Henderson, 2019). Through the new technique of MSNA-coupled functional magnetic resonance imaging, activity within several cortical and subcortical structures, many of which are sites of central adrenergic innervation, have been shown to correspond to MSNA bursts (Macefield & Henderson, 2019). These findings are particularly relevant to clinical populations in whom central adrenergic and peripheral sympathetic dysregulation are concurrent, such as in individuals with chronic anxiety-related disorders (Bigalke & Carter, 2021). Moreover, previous studies have not investigated the influence of cortical structures on underlying postganglionic recruitment patterns, which might be a more sensitive measure of sympathetic dysregulation in comparison to traditional integrated MSNA assessment in these clinical populations (Bigalke & Carter, 2021). Disentangling the central regions involved in peripheral sympathetic postganglionic governance is a necessary step to provide mechanistic insight into therapeutic targets for populations with central and peripheral sympathetic dysregulation. In a recent study published in The Journal of Physiology, Klassen et al. (2024) investigated the impact of central adrenergic activity on peripheral sympathetic outflow in humans using two new approaches: (i) pharmacological activation of central α2-adrenergic receptors; and (ii) quantification of sympathetic neuronal subpopulation recruitment patterns using advanced action potential (AP) clustering analysis (Klassen et al., 2024; Yoo et al., 2020). Central α2-adrenergic receptors are primarily inhibitory, thus evoking a sympatholytic effect within the brain. The authors sought to examine the effects of central α2-adrenergic agonism on microneurographic recordings of MSNA and hypothesized that infusion of dexmedetomidine, an α2-adrenergic receptor agonist, would: (i) attenuate sympathetic AP discharge and recruitment; and (ii) reduce AP latency through inhibition of slower-conducting adrenergic neurons. To test their hypotheses, continuous blood pressure, heart rate and MSNA recordings were obtained in eight healthy individuals (three males and five females) throughout a baseline period and subsequent intravenous dexmedetomidine hydrochloride (i.e. α2-adrenergic agonist) infusion. Uniform reductions in blood pressure and integrated MSNA were observed following dexmedetomidine infusion, and these reductions were primarily attributable to ordered de-recruitment of large APs (which generally exhibit a low probability of firing), followed by highly active, medium-sized APs. It might be expected that de-recruitment of large APs would result in prolonged AP latency, but the opposite was observed (i.e. reduced time delay). As alluded to by Klassen et al. (2024), this might represent a direct impact of central α2-adrenergic activity on the temporal coding of sympathetic fibres. The authors observed a downward shift in the inverse relationship between AP cluster size and latency during dexmedetomidine infusion, supporting their interpretation of a direct impact of α2-agonism on central processing latencies or synaptic delays. However, the data also indicated that AP incidence was reduced primarily in the normalized AP clusters 1−3, while it remained unchanged in clusters 4 and 5 (fig. 5 of Klassen et al. 2024). This ordered de-recruitment might inadvertently have led to a more proportionate contribution of each AP cluster (including larger AP clusters) to the overall number of APs, whereas, in the absence of α2-adrenergic agonism, most APs are medium in size, with longer latencies. This equal contribution of AP clusters following α2-agonism to the calculated latency might also explain, in part, the reduction in AP latency. Participants also performed a Valsalva manoeuvre (VM), which provides a dynamic assessment of baroreflex regulation of peripheral sympathetic outflow. The reduction observed in postganglionic sympathetic discharge at rest was also evident during the VM. Furthermore, the discharge probability of medium-sized APs and the recruitment of larger APs was decreased during the VM despite significant blood pressure reductions. However, the VM-evoked reduction in AP latency was not altered by dexmedetomidine, although dynamic sympathetic AP baroreflex gain for medium-sized APs was attenuated. Thus, the authors reasonably speculate that mechanisms involving cortical command contribute to reductions in AP latency during the VM and function independently from baroreflex and α2-adrenergic mechanisms. Collectively, these findings suggest a complex relationship between higher cortical command, α2-adrenergic influences and baroreflex-mediated mechanisms that control postganglionic sympathetic discharge during physiological stress in humans. Dexmedetomidine can cause sedation, resulting in significant effects on consciousness. Levels of consciousness exert a profound impact on cardiovascular measures and sympathetic outflow (Somers et al., 1993). In the study by Klassen et al. (2024), sedation was monitored using the Ramsey scale and a visual analog scale ranging from 0 (very alert) to 100 (very sedated). At the end of the dexmedetomidine infusion, the participants were scored 3 (i.e. asleep, with brisk response to a loud voice) on the Ramsey scale and provided a visual analog scale arousal rating of 78 units, indicating apparent sedation. In prior studies in which microneurography was performed during sleep, a significant reduction in both blood pressure and MSNA was observed through progressively deeper stages of non-rapid eye movement (Somers et al., 1993). A Ramsey scale rating of 3 can be compared most aptly to early stages (i.e. stage I and II) of non-rapid eye movement sleep, in which participants generally exhibit abrupt awakening and responsiveness to loud perturbation and during which small reductions in blood pressure and integrated MSNA are observed (Somers et al., 1993). It is possible that a portion of the present alterations in AP cluster recruitment patterns is attributable to reduced levels of consciousness. However, evidence of an independent effect of α2-agonism on AP discharge and recruitment is bolstered by the fact that participants were fully conscious and able to maintain the necessary expiratory pressure to complete the 20 s VM, during which significant reductions in AP discharge remained apparent relative to baseline (Klassen et al., 2024). Given that AP discharge patterns during sleep in humans have not yet been assessed, it is difficult to state with certainty what proportion of the observed sympathoinhibition might be attributed to sedation levels, although the careful experimental design used by the research team strengthens a key role for α2-adrenergic activity on the observed sympathoinhibition independent of sedation levels. The findings of Klassen & colleagues (2024) might be extrapolated to inform sympathetic regulatory patterns in other clinical populations. In addition to their presence within the brainstem, α2-adrenergic receptors are expressed in numerous higher cortical areas (i.e. insular, cingulate and prefrontal cortices). Prior studies have suggested an association between activity within areas including the prefrontal, insular and anterior cingulate cortices and peripheral sympathetic outflow (Macefield & Henderson, 2019). Dysregulation within many of these brain regions has also been implicated in the pathogenesis of anxiety and stress-related disorders, populations in whom cardiovascular risk is elevated, probably owing to sympathetic dysregulation (Bigalke & Carter, 2021). Notably, although resting integrated MSNA appears largely unchanged across anxiety-related disorders in comparison to healthy control subjects, alterations in MSNA burst strength, single-unit activity and AP recruitment strategies have been reported in populations with generalized anxiety disorder, panic disorder and post-traumatic stress disorder (PTSD) (Bigalke & Carter, 2021). Yoo et al. (2020) were the first to investigate sympathetic AP recruitment patterns in a population of women with PTSD using similar analyses to that in the study by Klassen et al. (2024). The authors observed a significant elevation in AP discharge at rest, in addition to an augmented firing rate and exaggerated AP recruitment in response to cold pressor stress in women with PTSD in comparison to women without PTSD. This elevated sympathetic recruitment in response to stress was attributed to an increase in the firing frequency of low-threshold axons and the increased recruitment of dormant, larger-diameter axons within the sympathetic nervous system. The pathological sympathetic postganglionic discharge patterns in adults with PTSD (i.e. increased AP firing frequency and exaggerated recruitment of larger axons) (Yoo et al., 2020) appears to mirror inversely the discharge patterns following α2-agonism via dexmedetomidine infusion (i.e. reduced AP firing frequency and de-recruitment of large axons) (Klassen et al., 2024), suggesting a potential role for central α2-adrenergic dysfunction underlying sympathetic dysregulation present in anxiety/stress-related disorders (Bigalke & Carter, 2021) (Fig. 1). Notably, a core diagnostic feature of PTSD among other anxiety-related disorders is hyperarousal, which is characterized by symptoms such as irritability, sleep disturbances and agitation. Increased central adrenergic activity within the aforementioned brain regions has been implicated in the pathophysiology of hyperarousal and has been suggested to underlie the symptomology associated with these disorders. This notion is supported by the use of α2-adrenergic receptor agonists, such as clonidine, to reduce central adrenergic activity and alleviate symptoms such as nightmares within individuals with PTSD. Extrapolation of the findings of Klassen et al. (2024) might suggest that the beneficial effects of α2-agonists on the symptomology of chronic anxiety/stress related disorders is attributable, in part, to reduced sympathetic hyperarousal, and also that α2-agonism might provide the dual benefit of reducing sympathetic hyperactivity and cardiovascular risk in these populations (Fig. 1; Yoo et al., 2020; Bigalke & Carter, 2021). In summary, Klassen & colleagues (2024) are the first to provide an elegant characterization of the influence of central α2-adrenergic mechanisms on sympathetic postganglionic discharge patterns and governance. These findings support a clear sympatho-inhibitory role of central α2-adrenergic activity mediated through ordered de-recruitment of peripheral sympathetic neurons. This study improves our knowledge surrounding the neural correlates of peripheral sympathetic outflow in humans and provides the basis for future investigation into the role that α2-adrenergic receptors might have in the observed peripheral sympathetic dysregulation in populations with central adrenergic dysregulation. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare that they have no competing interests. All authors have approved the final version of the manuscript. All authors agree to accountability for the present work. All authors contributed significantly to the present work. None. We thank Drs Manda Keller-Ross, Ida Fonkoue and Jason Carter for their helpful feedback and assistance in manuscript preparation.