CB1 cannabinoid receptor agonists induce acute respiratory depression in awake mice.
Pharmacological research – April 01, 2025
Source: PubMed
Summary
Synthetic cannabinoids can lead to acute respiratory failure, a risk often overlooked with THC, the main compound in cannabis. This study revealed that both THC and another cannabinoid significantly reduced breathing in mice by acting on brain regions essential for respiration. Notably, they also interacted with opioid pathways, highlighting potential overdose risks.
Abstract
Recreational use of synthetic cannabinoid agonists (i.e., "spice compounds") that target the cannabinoid type 1 receptor (CB1) can cause acute respiratory failure in humans. However, Δ9-tetrahydrocannabinol (Δ9-THC), the major psychoactive phytocannabinoid in cannabis, is not traditionally thought to interact with the brain respiratory system, based largely upon sparse labeling of CB1 receptors in the medulla and relative safety suggested by widespread human use. Here we used whole body plethysmography and RNAscope in situ hybridization in mice to reconcile this conflict between conventional wisdom and human data. We examined the respiratory effects of the synthetic CB1 full agonist CP55,940 and Δ9-THC in male and female mice. CP55,940 and Δ9-THC potently and dose-dependently suppressed minute ventilation and tidal volume, decreasing measures of respiratory effort (i.e., peak inspiratory and expiratory flow). Both cannabinoids reduced respiratory frequency, decreasing inspiratory and expiratory time while markedly increasing inspiratory and expiratory pause. Respiratory suppressive effects were fully blocked by the CB1 antagonist AM251, were minimally impacted by the peripherally-restricted CB1 antagonist AM6545, and occurred at doses lower than those that produce cardinal behavioral signs of CB1 activation. Using RNAscope in situ hybridization, we also demonstrated extensive coexpression of Cnr1 (encoding the CB1 receptor) and Oprm1 (encoding the µ-opioid receptor) mRNA in respiratory cells in the medullary pre-Bötzinger complex, a critical nucleus of respiratory control. Our results show that mRNA for CB1 is present in respiratory cells in a medullary brain region essential for breathing and demonstrate that cannabinoids produce respiratory suppression via activation of central CB1 receptors.