Sympathetic nervous activation via thin‐fiber muscle afferents: the role of insulin

Stimulation of mechanical and chemical receptors within skeletal muscle evokes action potentials in thin-fibre afferents (i.e. group III and IV afferents), which project to the dorsal root ganglion (DRG) of the spinal cord and then to neurons in the medulla oblongata, resulting in an increase in sympathetic outflow to the cardiovascular system. This phenomenon is referred to as the exercise pressor reflex. Understanding the regulation of these somatosensory thin-fibre afferents has valuable physiological and practical implications, especially in some disease states. For example, a recent study found that insulin can augment the mechanical responsiveness of thin-fibre afferents at both the DRG and muscle tissue levels (Hotta et al., 2019). Thus, in addition to playing an important role in glucose homeostasis, insulin has been suggested to act within the central nervous system to elevate sympathetic nerve activity (Ward et al., 2011), as well as induce mechanical sensitization peripherally (Hotta et al., 2019). Taken together, it is likely that insulin contributes to pain sensation or nociception, and leading to exaggerated sympathetic nerve activity in type 2 diabetic (T2D) patients and/or in non-diabetic insulin resistance individuals. Based on these findings, the next logical step is to determine whether insulin can also affect sympathoexcitation through DRG neurons and thin-fibre muscle afferents in response to chemical stimuli. A recent publication in The Journal of Physiology, Hori et al. (2022) used an elegant, comprehensive and integrative approach to investigate the effects of insulin on chemically activated DRG neurons and muscle afferents of healthy rats. They also investigated whether insulin potentiates sympathetic nerve activity responses to capsaicin in decerebrate rats. In the first experiment, inward currents and membrane voltages were recorded from cultured small DRG neurons in vitro from preto post-application of insulin. The results of this experiment showed that capsaicin-activated current increased after the application of insulin in ∼54% of neurons, and it was significantly higher than in the controls. The second experiment investigated the effect of insulin in capsaicin-induced action potentials in thin-fibre muscle afferents, using an ex vivo recording of individual muscle group III and IV muscle afferents from isolated extensor digitorum longus muscle. They found that capsaicin-evoked action potential discharges increased after intramuscular injection of insulin and it was significantly higher than in the controls. Of notable interest, they observed that some capsaicin-insensitive group IV fibres responded to capsaicin after the injection of insulin, suggesting that insulin has the ability to convert capsaicin-insensitive group IV fibres to capsaicin-sensitive neurons. They did not find any effect of insulin on group III fibres in response to capsaicin. Finally, the authors investigated whether findings from in vitro and ex vivo experiments could be translated into in vivo experiments. They measured blood pressure and renal sympathetic nerve activity in decerebrate rats and used a reversible vascular occluder placed around the abdominal aorta and the inferior vena cava to trap the injected drugs in the hindlimb. First, the pressor response was evaluated following capsaicin administration into the arterial supply of the hindlimb after occluding the circulation. Then, insulin was injected intramuscularly into six sites on the triceps surae muscles after occlusion of the hindlimb circulation again. They found that intramuscular injection of insulin significantly increased the capsaicin-induced change in blood pressure and renal sympathetic nerve activity. Collectively, the study by Hori et al. (2022) provides a possible role for insulin in the regulation of peripherally sympathetic nervous activation via chemically sensitive thin-fibre muscle afferents. Although Hori et al. present a challenging translational study, care should be exercised in interpreting some of their results. Particular focus should be paid to the effects of insulin on the sympathetic activity responses to capsaicin, the use of an exogenous TRPV1 receptor agonist, and the possible interaction between TRPV1 receptors and mechanical channels on thin-fibre afferents. Hori et al. (2022) suggested that insulin significantly augmented the renal sympathetic nerve activity to capsaicin in decerebrate rats resulting in a significant augmentation of a blood pressure response. It is worthwhile to mention that they did not indicate the statistical comparison by Bonferroni/Dunn’s test in the renal sympathetic activity response to capsaicin stimuli before and after insulin injection in the same group of rats. Thus, the interpretation of the data should be that the capsaicin-induced sympathetic activation after intramuscular injection of insulin was significantly greater than that after injection of the vehicle. Additionally, a major finding from Hori et al.’s study is that insulin can significantly potentiate the responsiveness of thin-fibre afferents to capsaicin in DRG and skeletal muscle tissue due to TRPV1 sensitization. However, the TRPV1 receptors were activated by an exogenous agonist (i.e. capsaicin), which is an active component of chilli peppers. Thus, the question that arises is how the insulin signalling system may modify the sensitivity in somatosensory thin-fibre muscle afferents when TRPV1 receptors are activated by endogenous signalling (i.e. heat, acidosis or endogenous agonist). With this in mind, further studies are necessary to provide the role of insulin in the sympathoexcitation to a physiological chemical stimulus of thin-muscle afferent fibres, and how insulin alters the activity of TRPV1 receptors. Hotta et al. first provided a novel role for insulin in the regulation of mechanical