Brain Penetrant, but not Peripherally Restricted, Synthetic Cannabinoid 1 Receptor Agonists Promote Morphine-Mediated Respiratory Depression

Introduction: Cannabis acceptance and use continues to rise despite the gaps in knowledge regarding the mechanisms of cannabinoids and the endocannabinoid system in many physiological functions, including respiratory influence. Methods: With recent evidence of cannabinoid receptor 1 (CB1R) presence in the collection of respiratory neurons in the brainstem, as well as in the peripheral lung tissue, it is vital that the mechanisms involved in central and peripheral CB1R modulation of respiratory function be delineated. In this study we sought to define the roles of central versus peripheral CB1R activation on respiratory depression alone and in combination with morphine using whole body plethysmography. Results: We show that the peripherally restricted CB1 agonist (4-{2-[-(1E)-1[(4-propylnaphthalen-1-yl)methylidene]-1H-inden-3yl]ethyl}morpholine [PrNMI] 0.3, 0.6, and 1 mg/kg) does not induce respiratory depression, while our previous studies showed that a central penetrating synthetic cannabinoid does induce respiratory depression. Significantly, the combination of morphine with the peripheral CB1 agonist, PrNMI, attenuated morphine-induced respiratory depression. Conclusions: These studies support that a peripherally restricted CB1R agonist may be a unique strategy to attenuate the respiratory depression associated with opioid therapy.