2019
DOI: 10.1126/science.aau0236
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Rapid molecular evolution of pain insensitivity in multiple African rodents

Abstract: Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and volta… Show more

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Cited by 63 publications
(110 citation statements)
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References 67 publications
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“…Consistent with this notion, NALCN knockout is lethal within a day after birth in mice due to disrupted respiratory rhythm (Lu et al, 2007). Furthermore, changes in NALCN expression and/or function have been implicated in other physiological processes such as motor function, pain sensitivity and circadian rhythm in animals (Lear et al, 2005, Yeh et al, 2008, Xie et al, 2013, Flourakis et al, 2015, Gao et al, 2015, Eigenbrod et al, 2019. In humans, accumulating evidence shows that mutations in NALCN cause severe congenital neurodevelopmental disorders (Al-Sayed et al, 2013, Chong et al, 2015, Bramswig et al, 2018, thus underlining its physiological significance.…”
Section: Introductionmentioning
confidence: 94%
See 1 more Smart Citation
“…Consistent with this notion, NALCN knockout is lethal within a day after birth in mice due to disrupted respiratory rhythm (Lu et al, 2007). Furthermore, changes in NALCN expression and/or function have been implicated in other physiological processes such as motor function, pain sensitivity and circadian rhythm in animals (Lear et al, 2005, Yeh et al, 2008, Xie et al, 2013, Flourakis et al, 2015, Gao et al, 2015, Eigenbrod et al, 2019. In humans, accumulating evidence shows that mutations in NALCN cause severe congenital neurodevelopmental disorders (Al-Sayed et al, 2013, Chong et al, 2015, Bramswig et al, 2018, thus underlining its physiological significance.…”
Section: Introductionmentioning
confidence: 94%
“…Two decades have passed since NALCN was first cloned, but functional expression of the channel in heterologous systems is still hampered by issues such as low levels of current (Swayne et al, 2009, Funato et al, 2016, Eigenbrod et al, 2019 and absence of NALCN-specific currents (Lee et al, 1999, Boone et al, 2014, Egan et al, 2018. Given the ample evidence supporting overlapping spatiotemporal gene expression profiles for NALCN, UNC79, UNC80 and FAM155A in Drosophila and mouse (Ghezzi et al, 2014, Lutas et al, 2016, their functional interdependence in Drosophila (Flourakis et al, 2015, Lear et al, 2013, C. elegans (Jospin et al, 2007, Humphrey et al, 2007, Yeh et al, 2008, Xie et al, 2013 and mouse (Lu et al, 2009, Lu et al, 2010 and the physical interactions between these proteins in vitro and in vivo (Lu et al, 2009, Lu et al, 2010, Xie et al, 2013, we set out to test the effect of co-expressing these proteins in different heterologous systems.…”
Section: Unc79 Unc80 and Fam155a Are Crucial For Nalcn Functionmentioning
confidence: 99%
“…Capsaicin robustly activates naked mole-rat polymodal C-fibers as determined by direct electrophysiological recordings with the ex vivo skin-nerve preparation and patch clamp recordings from isolated DRG neurons (Park et al 2008;Smith et al 2011;Omerbašić et al 2016). However, despite the fact naked mole-rat nociceptors are activated by capsaicin, foot pad injection of capsaicin fails to evoke any licking behavior in naked mole-rats (Park et al 2008;Eigenbrod et al 2019). In addition, whereas administration of capsaicin causes sensitization of the response to heat (thermal hyperalgesia), this phenomenon also does not occur in naked mole-rats (Park et al 2008).…”
Section: Nociceptor Function and Nocifensive Behaviors In Naked Mole-mentioning
confidence: 99%
“…In addition to changes in acute nociception, a variety of inflammatory stimuli have been used to examine the development of hyperalgesia in naked mole-rats. Formalin is a substance that evokes acute and late phases of nocifensive behaviors, which although occurring in the naked molerat are diminished compared to in mice (Park et al 2008;Eigenbrod et al 2019). The effects of a variety of analgesics and anti-inflammatory agents have been tested in the formalin model and the results can be summarized as follows: opioid receptor agonists and nefopam decrease both early and late phases of the pain response, whereas paracetamol, naproxen and dexamethasone only the late phase (Karim et al 1993;Kanui et al 1993;Towett et al 2009), i.e., compounds whose mechanism of action is predominantly anti-inflammatory only affect the late phase.…”
Section: Inflammatory Pain In Naked Mole-ratsmentioning
confidence: 99%
“…We likewise found here that TMEM206/ASOR channels of that species display normal pH-sensitivity. The pH-insensitivity of mole-rats may rather be due to a changed pH-sensitivity of the Na + -channel Na v 1.7 [54,55].…”
Section: Role Of Acid-activated Chloride Currentmentioning
confidence: 99%