Novel Approaches to Improving Opioid Analgesic Therapy

Abstract

Despite their extensive side effect profile and potential for abuse, clinically used opioids such as morphine are still the most effective analgesics for most chronic pain patients. A negative stigma has been cast over opioids due to the recent opioid epidemic, which has claimed hundreds of thousands of lives over the past few decades in the United States alone. Despite this, there is still great potential for the use of these drugs if negative side effect profiles, especially reward and addiction, can be reduced or eliminated. Here we identify a pharmacological and non-pharmacological means for enhancing analgesic potency while reducing side effect profiles attributed to systemic morphine. We have uncovered a novel regulator of downstream mu opioid receptor (MOR) signaling within the spinal cord, heat shock protein 90 (HSP90). Within the spinal cord, HSP90 prevents MOR induced ERK MAPK phosphorylation which otherwise activates RSK2 and subsequent translation, leading to enhanced morphine induced anti-nociception. By selectively inhibiting HSP90 within the spinal cord, morphine induced anti-nociception is elevated without impacting side effects, and therefore allows for a dose reduction strategy while achieving equi-efficacious anti-nociception. Additionally, we have uncovered a novel consequence of dietary intervention on opioid pharmacology. Through daily intermittent fasting (IF), morphine induced anti-nociception is enhanced and prolonged, while several side effects including reward, constipation, and tolerance are reduced. MOR functionality but not expression within various brain regions is altered due to daily IF which may account for the behavioral differences in systemic morphine treatments seen with IF. These two approaches attempt to alter opioid pharmacology not by modifications to new drugs, but by altering opioid physiology to maximize the desired effect of anti-nociception while reducing side effects. Together these novel approaches may allow for rapid translation into the clinic and lead to additional research efforts to improve existing opioids with the aim of treating chronic pain in patients while reducing side effects and abuse.