Interaction between delta opioid receptors and benzodiazepines in CO2-induced respiratory responses in mice

The false-suffocation hypothesis of panic disorder (Klein, 1993) suggested δ-opioid receptors as a possible source of the respiratory dysfunction manifested in panic attacks occurring in panic disorder (Preter and Klein, 2008). This study sought to determine if a lack of δ-opioid receptors in a mouse model affects respiratory response to elevated CO2, and whether the response is modulated by benzodiazepines, which are widely used to treat panic disorder. In a whole-body plethysmograph, respiratory responses to 5% CO2 were compared between δ-opioid receptor knockout mice and wild-type mice after saline, diazepam (1 mg/kg), and alprazolam (0.3 mg/kg) injections. The results show that lack of δ-opioid receptors does not affect normal response to elevated CO2, but does prevent benzodiazepines from modulating that response. Thus, in the presence of benzodiazepine agonists, respiratory responses to elevated CO2 were enhanced in δ-opioid receptor knockout mice compared to wild-type mice. This suggests an interplay between benzodiazepine receptors and δ-opioid receptors in regulating the respiratory effects of elevated CO2, which might be related to CO2 induced panic.

Research highlights
► Panic disorder is associated with a hyper-response to 5% CO2.
► Mice were found to respond to 5% CO2 by increasing respiratory tidal volume.
► This respiratory response was reduced by anxiolytic benzodiazepine treatment.
► Delta opioid receptors were not required for the response to CO2.
► Delta opioid receptors were required for the anxiolytic benzodiazepine response.