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 voltage-gated sodium channel Nav1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.
Subject(s)
Evolution, Molecular , Mole Rats/physiology , NAV1.7 Voltage-Gated Sodium Channel/genetics , Nociceptive Pain/genetics , Pain Threshold , TRPA1 Cation Channel/genetics , Animals , Binding Sites , Capsaicin/pharmacology , Hydrochloric Acid/pharmacology , Insect Bites and Stings/genetics , Insect Bites and Stings/immunology , Isothiocyanates/pharmacology , Mole Rats/genetics , Mole Rats/immunology , Nociceptive Pain/chemically induced , Nociceptors/drug effects , Nociceptors/physiology , Protein Conformation , Sequence Analysis, RNA , Species Specificity , TRPA1 Cation Channel/chemistryABSTRACT
The African naked mole-rat's (Heterocephalus glaber) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.
Subject(s)
Adaptation, Physiological , Anaerobiosis , Brain/physiology , Fructose/metabolism , Glycolysis , Mole Rats/metabolism , Oxygen/metabolism , Animals , Brain/metabolism , Fructokinases/metabolism , Glucose Transporter Type 5/metabolism , Lactic Acid/metabolism , Mice , Myocardium/metabolism , Sucrose/metabolismABSTRACT
The naked mole-rat is a subterranean rodent lacking several pain behaviors found in humans, rats, and mice. For example, nerve growth factor (NGF), an important mediator of pain sensitization, fails to produce thermal hyperalgesia in naked mole-rats. The sensitization of capsaicin-sensitive TRPV1 ion channels is necessary for NGF-induced hyperalgesia, but naked mole-rats have fully functional TRPV1 channels. We show that exposing isolated naked mole-rat nociceptors to NGF does not sensitize TRPV1. However, the naked mole-rat NGF receptor TrkA displays a reduced ability to engage signal transduction pathways that sensitize TRPV1. Between one- and three-amino-acid substitutions in the kinase domain of the naked mole-rat TrkA are sufficient to render the receptor hypofunctional, and this is associated with the absence of heat hyperalgesia. Our data suggest that evolution has selected for a TrkA variant that abolishes a robust nociceptive behavior in this species but is still compatible with species fitness.
