Amiloride modulation of carbon dioxide hypersensitivity and thermal nociceptive hypersensitivity induced by interference with early maternal environment

J Psychopharmacol. 2019 Jan;33(1):101-108. doi: 10.1177/0269881118784872. Epub 2018 Jul 3.


Background: Early life adversities are risk factors for anxiety disorders and for pain syndromes, which are, in turn, highly comorbid with anxiety disorders. Repeated cross-fostering mouse pups to adoptive lactating females induces epigenetic modification and heightened mRNA-expression of the acid-sensing-ion-channel-1 gene, altered nociception, and hypersensitivity to 6% carbon dioxide air mixtures, a trait marker of specific human anxiety disorders such as, most clearly and prominently, panic disorder.

Aims: We hypothesized that the acid-sensing ion channel inhibitor amiloride can modulate repeated cross-fostering animals' exaggerated responses to carbon dioxide and nociceptive thermal stimulation.

Methods: Respiratory carbon dioxide sensitivity was assessed by plethysmography during 6% carbon dioxide air mixture challenges, and nociception was assessed by latency of paw withdrawal to thermal stimulation, in repeated cross-fostering and control animals. To circumvent the blood-brain barrier, prior to testing, amiloride was nebulized in a plethysmograph. Data were analyzed by general linear models.

Results: Analyses of tidal volume responses to 6% carbon dioxide of animals pre-treated with nebulized amiloride/saline in a randomized crossover design showed significant modulatory effect of amiloride, and amiloride×repeated cross-fostering interaction. In contrast, repeated cross-fostering animals' responses to 6% carbon dioxide after intraperitoneal amiloride, saline, or no treatment, were no different. Analyses of responses to thermal stimuli showed a significant modulatory effect of nebulized amiloride, and repeated cross-fostering×amiloride interaction.

Conclusions: Single-dose nebulized amiloride decreased repeated cross-fostering animals' carbon dioxide sensitivity and nociception indices to levels that were no different from those of control animals. Inasmuch as these results pertain to human anxiety and/or pain hypersensitivity, our findings provide a rationale for studying inhaled amiloride in some anxiety disorders and/or pain syndromes.

Keywords: Neurophysiology; biomarkers; health sciences; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acid Sensing Ion Channel Blockers / pharmacology*
  • Amiloride / pharmacology*
  • Animals
  • Anxiety / drug therapy
  • Carbon Dioxide / administration & dosage*
  • Female
  • Hot Temperature
  • Lactation
  • Male
  • Mice
  • Nociception / drug effects*
  • Tidal Volume / drug effects


  • Acid Sensing Ion Channel Blockers
  • Carbon Dioxide
  • Amiloride