Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin

Steen, Kay H.; Reeh, Peter W.

doi:10.1016/0304-3940(93)90184-m

Cited by 177 publications

(90 citation statements)

References 12 publications

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“…Therefore, the role of ASIC3 in cutaneous nociception may depend on a specific phase of the inflammatory process. That ASIC3 participates in cutaneous nociception in both rats and mice is reminiscent of the findings that acid injection in humans activates nociceptors and produces pain that can be attenuated by the DEG/ENaC inhibitor amiloride (46)(47)(48). These data suggest that drugs targeting ASIC3 channels hold the potential to be effective analgesics in humans.…”

Section: Cutaneous Nociceptionmentioning

confidence: 80%

ASIC3 Channels in Multimodal Sensory Perception

2010

ACS Chem. Neurosci.

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Acid-sensing ion channels (ASICs), which are members of the sodium-selective cation channels belonging to the epithelial sodium channel/degenerin (ENaC/ DEG) family, act as membrane-bound receptors for extracellular protons as well as nonproton ligands. At least five ASIC subunits have been identified in mammalian neurons, which form both homotrimeric and heterotrimeric channels. The highly proton sensitive ASIC3 channels are predominantly distributed in peripheral sensory neurons, correlating with their roles in multimodal sensory perception, including nociception, mechanosensation, and chemosensation. Different from other ASIC subunit composing ion channels, ASIC3 channels can mediate a sustained window current in response to mild extracellular acidosis (pH 7.3-6.7), which often occurs accompanied by many sensory stimuli. Furthermore, recent evidence indicates that the sustained component of ASIC3 currents can be enhanced by nonproton ligands including the endogenous metabolite agmatine. In this review, we first summarize the growing body of evidence for the involvement of ASIC3 channels in multimodal sensory perception and then discuss the potential mechanisms underlying ASIC3 activation and mediation of sensory perception, with a special emphasis on its role in nociception. We conclude that ASIC3 activation and modulation by diverse sensory stimuli represent a new avenue for understanding the role of ASIC3 channels in sensory perception. Furthermore, the emerging implications of ASIC3 channels in multiple sensory dysfunctions including nociception allow the development of new pharmacotherapy.

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Section: Cutaneous Nociceptionmentioning

confidence: 80%

ASIC3 Channels in Multimodal Sensory Perception

2010

ACS Chem. Neurosci.

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“…: 45-44608223; Fax: 45-44608080; E-mail: pka@neurosearch.dk. 1 The abbreviations used are: ASIC, acid-sensing ion channel; ENaC, epithelial Na ϩ channel; DEG, degenerin; FaNaC, Phe-Met-Arg-Pheamide-activated Na ϩ channel; CHO, Chinese hamster ovary; DRG, dorsal root ganglion; MES, 4-morpholineethanesulfonic acid.…”

Section: Methodsmentioning

confidence: 99%

“…It is well established that tissue acidification, which may be present in inflammatory and ischemic conditions, causes pain (1)(2)(3). In line with this, peripheral sensory neurons exhibit sensitivity toward acid by activating several types of depolarizing currents (4 -6).…”

mentioning

confidence: 96%

pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits

Hesselager

Timmermann

Ahring

2004

Journal of Biological Chemistry

299

347

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The exact subunit combinations of functional native acid-sensing ion channels (ASICs) have not been established yet, but both homomeric and heteromeric channels are likely to exist. To determine the ability of different subunits to assemble into heteromeric channels, a number of ASIC1a-, ASIC1b-, ASIC2a-, ASIC2b-, and ASIC3-containing homo-and heteromeric channels were studied by whole-cell patch clamp recordings with respect to pH sensitivity, desensitization kinetics, and level of sustained current normalized to peak current. Analyzing and comparing data for these three features demonstrated unique heteromeric channels in a number of co-expression experiments. Formation of heteromeric ASIC1a؉2a and ASIC1b؉2a channels was foremost supported by the desensitization characteristics that were independent of proton concentration, a feature none of the respective homomeric channels has. Several lines of evidence supported formation of ASIC1a؉3, ASIC1b؉3, and ASIC2a؉3 heteromeric channels. The most compelling was the desensitization characteristics, which, besides being proton-independent, were faster than those of any of the respective homomeric channels. ASIC2b, which homomerically expressed is not activated by protons per se, did not appear to form unique heteromeric combinations with other subunits and in fact appeared to suppress the function of ASIC1b. Co-expression of three subunits such as ASIC1a؉2a؉3 and ASIC1b؉2a؉3 resulted in data that could best be explained by coexistence of multiple channel populations within the same cell. This observation seems to be in good agreement with the fact that ASIC-expressing sensory neurons display a variety of acid-evoked currents.It is well established that tissue acidification, which may be present in inflammatory and ischemic conditions, causes pain (1-3). In line with this, peripheral sensory neurons exhibit sensitivity toward acid by activating several types of depolarizing currents (4 -6). Although the repertoire of ion channels responsible for these currents is not fully known, the family of acid-sensing ion channels (ASICs) 1 is believed to be an important constituent. The ASIC family is a member of the ENaC/ DEG superfamily, which also includes the amiloride-sensitive epithelial sodium channels (ENaCs), the mechanically gated degenerins of Caenorhabditis elegans (DEGs), and a neuropeptide-gated channel of Helix aspersa (FaNaC). The membrane topology of all channels within this superfamily comprises two transmembrane domains, intracellular N and C termini and a large extracellular loop with a number of conserved cysteine residues (7). Currently, four genes encoding six ASIC transcripts have been cloned and characterized from mammalian organisms. ASIC1a (BNaC2) and ASIC1b (ASIC1␤) are the products of alternatively spliced transcripts of the ASIC1 gene that differ in the N-terminal region, including the first transmembrane domain and the proximal part of the large extracellular domain (8 -10). ASIC2a (BNaC1, MDEG) and ASIC2b (MDEG2) are alternatively spliced forms of ...

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“…Low pH can elicit pain, and decreases in tissue pH occur in a number of biological settings (Hood et al, 1988;Pan et al, 1988;Issberner et al, 1996;Reeh and Steen, 1996). In humans, intramuscular infusion of acidic buffer causes painful sensations and increased sensitivity to mechanical stimulation (Steen and Reeh, 1993;Issberner et al, 1996). Secondary hyperalgesia can also be elicited by intramuscular injections of inflammatory agents such as carrageenan (Radhakrishnan et al, 2003).…”

Section: Muscle-derived Mechanical Secondary Hyperalgesiamentioning

confidence: 99%

Neurotrophin-3 Reverses Chronic Mechanical Hyperalgesia Induced by Intramuscular Acid Injection

Gandhi

Ryals²,

Wright³

2004

J. Neurosci.

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Injection of acid into the gastrocnemius muscle results in a persistent, mechanical hyperalgesia of the hindpaw (Sluka et al., 2001). Here, the ability of neurotrophins to alter the development of this secondary hyperalgesia was assessed using transgenic mice and exogenous neurotrophin administration. Acid-induced hyperalgesia was measured in wild-type and transgenic mice that overexpress neurotrophin-3 (NT-3) in muscle (myo/NT-3 mice). Mechanical and thermal sensitivity of the hindpaws were assessed after injections of acidic saline, pH 4, into the right medial gastrocnemius. Wild-type mice exhibited mechanical but not thermal hyperalgesia in both paws 1 d after acid injection. In contrast, myo/NT-3 mice developed a transient mechanical hyperalgesia in both paws that disappeared by 2-3 d. The reversal of hyperalgesia in myo/NT-3 mice could be mimicked by intramuscular administration of exogenous NT-3 to acid-injected mice but not by other neurotrophins. The route of NT-3 administration appears critical, because intrathecal or intraperitoneal delivery were ineffective. The hyperalgesia could only be reversed by NT-3 treatment concurrent with acid injection and not after the emergence of hyperalgesia. The acid-induced hyperalgesia did not redevelop after the termination of NT-3 treatment, suggesting that NT-3 permanently reversed the hyperalgesia. Consistent with the behavioral data, paw palpation of acid-injected mice significantly increased Fos expression in the spinal cord of wild-type but not myo/NT-3 or NT-3-injected mice. The attenuation of hyperalgesia suggests that NT-3 may be a modulator of muscle-derived pain, and NT-3 may suppress events that lead to secondary hyperalgesia triggered by insult to muscle afferents.

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Sustained graded pain and hyperalgesia from harmless experimental tissue acidosis in human skin

Cited by 177 publications

References 12 publications

ASIC3 Channels in Multimodal Sensory Perception

ASIC3 Channels in Multimodal Sensory Perception

pH Dependency and Desensitization Kinetics of Heterologously Expressed Combinations of Acid-sensing Ion Channel Subunits

Neurotrophin-3 Reverses Chronic Mechanical Hyperalgesia Induced by Intramuscular Acid Injection

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