Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat

Am J Physiol Regul Integr Comp Physiol. 2020 Apr 1;318(4):R712-R721. doi: 10.1152/ajpregu.00251.2019. Epub 2020 Jan 22.


Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%-10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40-400 μg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%-10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a "normal" HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.

Keywords: body temperature; hypercapnic metabolic response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carbon Dioxide / administration & dosage
  • Carbon Dioxide / pharmacology*
  • Hypercapnia*
  • Male
  • Mole Rats*
  • Plethysmography
  • Receptors, Neurokinin-1 / metabolism*
  • Respiratory Physiological Phenomena*
  • Substance P / deficiency
  • Substance P / metabolism*


  • Receptors, Neurokinin-1
  • Carbon Dioxide
  • Substance P