Lactic acid produced by anaerobic metabolism during cardiac ischemia is among several compounds suggested to trigger anginal chest pain; however, the pH reached when a coronary artery is occluded (pH 7.0 to 6.7) can also occur during systemic acidosis, which causes no chest pain. Here we show that lactate, acting through extracellular divalent ions, dramatically increases activity of an acid-sensing ion channel (ASIC) that is highly expressed on sensory neurons that innervate the heart. The effect should confer upon neurons that express ASICs an extra sensitivity to the lactic acidosis of local ischemia compared to acidity caused by systemic pathology.

The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810,AMG 9810 is a competitive antagonist of capsaicin activation (IC 50 value for human TRPV1, 24.5 Ϯ 15.7 nM; rat TRPV1, 85.6 Ϯ 39.4 nM) and blocks all known modes of TRPV1 activation, including protons (IC 50 value for rat TRPV1, 294 Ϯ 192 nM; human TRPV1, 92.7 Ϯ 72.8 nM), heat (IC 50 value for rat TRPV1, 21 Ϯ 17 nM; human TRPV1, 15.8 Ϯ 10.8 nM), and endogenous ligands, such as anandamide, N-arachidonyl dopamine, and oleoyldopamine. AMG 9810 blocks capsaicin-evoked depolarization and calcitonin gene-related peptide release in cultures of rat dorsal root ganglion primary neurons. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG 9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. At effective doses, AMG 9810 did not show any significant effects on motor function, as measured by open field locomotor activity and motor coordination tests. AMG 9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.Activation of peripheral nociceptors in humans by capsaicin results in burning pain (Park et al., 1995). Capsaicin, and its ultrapotent analog resiniferatoxin, aided the identification and characterization of the vanilloid receptor 1 (aka VR1 and TRPV1). TRPV1 is a nonselective cation channel with high permeability to calcium (Caterina et al., 1997) and belongs to a superfamily of ion channels known as the transient receptor potential channels or TRPs (Clapham et al., 2001). In addition to activation by exogenous agonists such as capsaicin and resiniferatoxin, TRPV1 can be activated by physical stimuli, such as heat (Ͼ42°C) and protons (pH 5). Based on their structural similarity to capsaicin, several endogenous ligands have been proposed that include anandamide (AEA), 12-hydroperoxy-5,8,10,14-eicosatetraenoic acid,N-arachidonyl dopamine (NADA), N-oleoyldopamine (OLDA), and products of lipoxygenases (Hwang et al., 2000;Olah et al., 2001;Huang et al., 2002;Chu et al., 2003). TRPV1 is up-regulated during inflammation (Ji et al., 2002), and channel activity is modulated by the action of inflammaArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org.doi :

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.