ASIC3, an Acid-Sensing Ion Channel, is Expressed in Metaboreceptive Sensory Neurons

Abstract

BackgroundASIC3, the most sensitive of the acid-sensing ion channels, depolarizes certain rat sensory neurons when lactic acid appears in the extracellular medium. Two functions have been proposed for it: 1) ASIC3 might trigger ischemic pain in heart and muscle; 2) it might contribute to some forms of touch mechanosensation. Here, we used immunocytochemistry, retrograde labelling, and electrophysiology to ask whether the distribution of ASIC3 in rat sensory neurons is consistent with either of these hypotheses.ResultsLess than half (40%) of dorsal root ganglion sensory neurons react with anti-ASIC3, and the population is heterogeneous. They vary widely in cell diameter and express different growth factor receptors: 68% express TrkA, the receptor for nerve growth factor, and 25% express TrkC, the NT3 growth factor receptor. Consistent with a role in muscle nociception, small (<25 μm) sensory neurons that innervate muscle are more likely to express ASIC3 than those that innervate skin (51% of small muscle afferents vs. 28% of small skin afferents). Over 80% of ASIC3+ muscle afferents co-express CGRP (a vasodilatory peptide). Remarkably few (9%) ASIC3+ cells express P2X3 receptors (an ATP-gated ion channel), whereas 31% express TRPV1 (the noxious heat and capsaicin-activated ion channel also known as VR1). ASIC3+/CGRP+ sensory nerve endings were observed on muscle arterioles, the blood vessels that control vascular resistance; like the cell bodies, the endings are P2X3- and can be TRPV1+. The TrkC+/ASIC3+ cell bodies are uniformly large, possibly consistent with non-nociceptive mechanosensation. They are not proprioceptors because they fail two other tests: ASIC3+ cells do not express parvalbumin and they are absent from the mesencephalic trigeminal nucleus.ConclusionOur data indicates that: 1) ASIC3 is expressed in a restricted population of nociceptors and probably in some non-nociceptors; 2) co-expression of ASIC3 and CGRP, and the absence of P2X3, are distinguishing properties of a class of sensory neurons, some of which innervate blood vessels. We suggest that these latter afferents may be muscle metaboreceptors, neurons that sense the metabolic state of muscle and can trigger pain when there is insufficient oxygen.

ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation

“…Further, 80% of ASIC3-positive DRG neurons express calcitonin generelated peptide, and nerve terminals co-expressing ASIC3 and CGRP are found in primary afferents innervating muscle arterioles (Molliver et al, 2005). In contrast, few proprioceptors express ASIC3 (Molliver et al, 2005). Together, these data suggest that ASIC3 in primary afferent fibers innervating muscle is critical to development of mechanical hyperalgesia as a result of muscle insult.…”

“…In support of our results Mogil and colleagues (2005) showed development of mechanical hyperalgesia similar to that observed in our prior studies in ASIC3+/+ mice using C57BL/6J mice. Recently, McCleskey and colleagues (Molliver et al, 2005) show that ASIC3 is expressed in 51% of small nociceptive DRG neurons that innervate muscle compared to only 28% of small nociceptive DRG neurons that innervate skin. Further, 80% of ASIC3-positive DRG neurons express calcitonin generelated peptide, and nerve terminals co-expressing ASIC3 and CGRP are found in primary afferents innervating muscle arterioles (Molliver et al, 2005).…”

“…Recently, McCleskey and colleagues (Molliver et al, 2005) show that ASIC3 is expressed in 51% of small nociceptive DRG neurons that innervate muscle compared to only 28% of small nociceptive DRG neurons that innervate skin. Further, 80% of ASIC3-positive DRG neurons express calcitonin generelated peptide, and nerve terminals co-expressing ASIC3 and CGRP are found in primary afferents innervating muscle arterioles (Molliver et al, 2005). In contrast, few proprioceptors express ASIC3 (Molliver et al, 2005).…”

Elevated brain lactate responses to neural activation in panic disorder: a dynamic 1H-MRS study

“…66 These peripheral acid sensing ion channels appear to mediate distressing interoceptions associated with lactate accumulation, including anginal pain. 67 These or related mechanisms could mediate an association between elevated lactate responses and 'spontaneous' panic attacks triggered by chemosensitive arousal systems in PD patients.…”

Morphological and functional diversity of first-order somatosensory neurons

“…Retrograde labeling of dental pulp afferents permitted the identification of a population of nociceptors which was found to contain small, medium, and large diameter cell bodies (Silbert et al 2003). In other studies, expression of ASIC3, a putative nociceptive marker (McCleskey and Gold 1999;Naves and McCleskey 2005), was found in larger neurons that did not express P2X3 currents (Molliver et al 2005;Moraes et al 2014). These large neurons, which respond to reduced pH, lactate, and ATP released during ischemia, may correspond to muscle metaboreceptors or nociceptors Yagi et al 2006;Birdsong et al 2010;Light et al 2008).…”