Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat

Abstract

SummaryThe 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.

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

“…18 Furthermore, response to low pH has been shown to be sensitized by inflammatory mediators. [19][20][21][22][23][24] We and others have demonstrated expression and function of TRPV1 and ASICs within articular sensory neurones, [25][26][27] and both TRPV1 and ASIC3 are upregulated in different inflammatory models, suggesting their involvement in inflammatory pain. 26,28,29 A common model for inflammatory arthritis involves intraplantar/intraarticular injection of complete Freund's adjuvant (CFA), 30 which although not replicating autoimmunity does provide a robust model of RA-like arthritis: T cell-mediated pathogenesis, leukocyte invasion, synoviocyte hyperplasia, pannus formation and disrupted gait.…”

“…Sensory neurones express several acid sensors: acid‐sensing ion channels (ASICs), transient receptor potential vanilloid 1 (TRPV1), proton‐sensing GPCRs and certain background K + channels 18. Furthermore, response to low pH has been shown to be sensitized by inflammatory mediators 19, 20, 21, 22, 23, 24…”

Expression of acid-sensing ion channels and selection of reference genes in mouse and naked mole rat

“…In the peripheral nervous system, ASICs are expressed by sensory neurons of the dorsal root ganglia (DRG) [13–16] and are involved in nociception and mechanosensation [17, 18]. Interestingly, the naked mole-rat ( Heterocephalus glaber ) shows no nocifensive response to acid due to a lack of activation of cutaneous sensory neurons [19], even though DRG neurons have ASIC-like currents and cloned ASIC1a and ASIC1b, as well as TRPV1, have biophysical properties that are indistinguishable from those of mice [14, 20]. Behavioral acid insensitivity is accounted for by a genetic variation in the voltage-gated Na + channel subunit 1.7 (NaV1.7), which confers enhanced acid inhibition [14].…”

Brain atlas of the African mole‐ratFukomys anselli

“…We were not able to identify the paratrigeminal nucleus in the Ansell's mole‐rat, a brain area involved in the integration of somatosensory reflexes related to nociceptive, respiratory, and cardiovascular mechanisms (Caous, de Sousa Buck, & Lindsey, ). This nucleus was also not demonstrated in the naked mole‐rat (Xiao et al, ), a species for which reduced pain sensitivity has been reported (Omerbašić et al, ; Park et al, ).…”