Opioids, Breathing, and the Prefrontal Cortex: Relevance for the Behavioral Control of Breathing

This dissertation was motivated by the societal context of the threat to public health posed by the opioid and obesity epidemics. Both opioids and obesity have deleterious effects on breathing. Breathing is a key component of an organism’s behavioral state and its survival. Significantly depressed breathing can lead to a hypoxic brain state resulting in decreased cognition and ultimately death. Opioids are effective for the management of acute pain, but they depress breathing and behavioral arousal and can cause opioid use disorder. Obesity is often comorbid with chronic pain and respiratory disorders such as sleep disordered breathing. Leptin is a hormone produced by adipose tissue that stimulates breathing by acting on leptin receptors in the central nervous system. Leptin has been implicated as a modulator of the physiological intersections between opioids and obesity, but the underlying mechanisms are not known. The prefrontal cortex facilitates executive function and integrates autonomic output with behavioral states. The prefrontal cortex is particularly sensitive to hypoxic episodes caused by opioids or sleep disordered breathing secondary to obesity. Furthermore, opioid use disorder and obesity are both diseases that can be attributed to loss of prefrontal cortex regulation of behavioral reward pathways. Thus, the prefrontal cortex is one brain region of interest in the study of the behavioral control of breathing as well as opioid and obesity-induced changes in breathing. The studies in this dissertation describe the respiratory effects of opioids and obesity. After a brief introduction, Chapters 2, 3, and 4 show that obese mice with dysfunctional leptin receptors exhibit reduced thermal nociception and more pronounced buprenorphine-induced disruptions in breathing. Chapter 5 demonstrates for the first time in B6 mice that fentanyl and acetylcholine in the prefrontal cortex modulate breathing. These results encourage future studies characterizing the complete mechanism by which the prefrontal cortex regulates the behavioral control of breathing. Taken together, the findings from this dissertation highlight leptin and the prefrontal cortex as potential targets for therapeutic interventions for opioid and obesity-induced changes in breathing.