Receptor synergy from thin fiber muscle afferents. Focus on "Dorsal Root Ganglion Neurons Innervating Skeletal Muscle Respond to Physiological Combinations of Protons, ATP, and Lactate Mediated by ASIC, P2X, and TRPV1".

In the recent article by Light et al., the authors identify the substances critical to signaling pain and fatigue in skeletal muscle. The identified substances act on Group III and IV fibers, which are thinly myelinated and unmyelinated, respectively, and correspond to their better known cutaneous counterparts, A and C fibers. Group III and IV afferents, often called thin fiber muscle afferents, comprise the afferent arm of the exercise pressor reflex (Coote and Pérez-González 1970; McCloskey and Mitchell 1972), which functions to increase arterial perfusion pressure and/ or cardiac output during exercise. Substantial evidence has accumulated in humans to show that thin fiber muscle afferents play an important role in evoking some of the cardiovascular and sympathetic neural responses to both dynamic and static exercise (Mitchell et al. 1989; Strange et al. 1993; Victor et al. 1989). Although both mechanical and metabolic stimuli are known to evoke the exercise pressor reflex, the latter have received the most attention because metabolic stimulation of thin fiber muscle afferents seems likely to signal the spinal cord and brain stem that blood/oxygen supply to the exercising muscles is inadequate to meet demand. One of the first to provide evidence for a “metabolic error signal” was Alam and Smirk, who showed that the pressor response to exercise was greater when the circulation to the working limb was occluded than when the circulation was allowed to flow freely (Alam and Smirk 1937). They also showed that the pressor response was partly maintained after the end of the exercise period if the circulation to the working muscles remained occluded (Alam and Smirk 1937). The maintained pressor response to exercise has been named the muscle metaboreflex and was attributed to trapped metabolites in the exercising muscles. Many investigators have attempted to discover the nature of the specific metabolite that evoked the muscle metaboreflex. The traditional approach has been to compare the pressor and often the sympathetic nerve responses to contraction of limb muscles before and after either blocking the receptors to a specific metabolite or blocking an enzyme within muscle that produces a metabolite. The findings from these types of experiments have been quite consistent, namely that blockade of one receptor on the endings of the thin fiber muscle afferents or the prevention of the production of a single metabolite by the exercising muscles has reduced the pressor response to contraction by about half. Unfortunately, this finding has been reported for several metabolites or their receptors, including prostaglandins (Hayes et al. 2006; Stebbins et al. 1988), bradykinin (Stebbins and Longhurst 1986), lactic acid (Hayes et al. 2007), and ATP (Hanna and Kaufman 2003). Using simple arithmetic one can easily see that adding the individual magnitudes of the reduction in the pressor response to exercise far exceeds 100%. Until now, the apparent problem in interpreting the data has received little attention. Light et al. have shown that the adequate stimuli to thin fiber muscle afferents are combinations of metabolites. Exposure of these cells to any one metabolite had only small stimulatory effects on the cells, whereas the combination of three had effects that exceeded the simple summation of each one individually. Specifically, Light et al. used calcium imaging of cultured dorsal root ganglion cells from mice to detect the specific agonists that stimulated them as well as antagonists to detect their receptors. In addition, these investigators found two populations of dorsal root ganglion cells arising from muscle. The first population was thought to detect levels of muscle metabolites that contribute to evoking the exercise pressor reflex but did not cause pain. The second was thought to detect painful levels of muscle metabolites, such as those produced by injury or ischemia. In particular the first finding, namely that combinations of protons, lactate, and ATP were required to activate dorsal root ganglion cells, is an important advance. This finding explains why blockade of one receptor on the endings of group III and IV muscle afferents or the production of one metabolite prevents a large percentage of the exercise pressor reflex. It also predicts that pain-induced responses arising from noxious stimulation of muscle should be greatly attenuated by blockade of one receptor; this prediction needs further confirmation. Every experimental preparation imposes limits on the interpretation of one’s findings, and this is certainly the case with those reported by Light et al. These limitations, however, are recognized by the authors and have been given the appropriate discussion. Nevertheless, it is still important to mention some of them here. First, Light et al. were stimulating and blocking receptors on cell bodies and not on the endings of group III and IV afferents in the interstitium of muscle. The receptor concentrations and affinities may differ between in vivo and cultured cell preparations, an effect that may in part be caused by differences in growth factors. Second, obviously one cannot identify afferents that respond to contraction when using cultured dorsal root ganglion cells, a limitation that makes it impossible to discern the relationship between metabolites and cells responsive to muscular contraction. Third, the preparation does not allow one to distinguish group III afferents from Address for reprint requests and other correspondence: M. P. Kaufman, Heart and Vascular Institute, Penn State College of Medicine, Hershey, Pennsylvania. J Neurophysiol 100: 1169–1170, 2008. First published June 25, 2008; doi:10.1152/jn.90693.2008.