Papers of the Week

Opioid crisis is a major threat of 21st century with a remarkable juxtaposition of use and abuse. Opioids are the most potent and efficacious class of analgesics but despite their proven therapeutic efficacy they have recently been degraded to third-line of therapy for the management of chronic pain in clinics. The reason behind is the development of potential side effects and tolerance after repeated dosing. Opioid tolerance is the major limiting factor leading to the treatment withdrawal, severe side effects due to dose escalation and sometimes even death of the patients. Every day more than 90 people die due to the overdose of opioids in America and similar trend has been seen across the globe. Researchers in past two decades are trying to dissect the neurobiological mechanism of opioid tolerance. Research on opioid tolerance shifted towards the CNS based adaptations because tolerance is much more than just being a cellular phenomenon. Thus, neurobiological adaptations associated with opioid tolerance are important to understand in order to set newer pain therapeutics. These adaptations are associated with the alterations in ascending and descending pain pathways, reward circuitry modulations, receptor desensitization and down-regulation, receptor internalization, heterodimerization and altered epigenetic regulation. The present review is focussed on novel circuitries in different brain areas such as periaqueductal gray (PAG), rostral ventromedial medulla (RVM), dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and nucleus accumbens (NAc) associated with opioid tolerance. Understanding the neurobiological modulations associated with chronic opioid exposure and tolerance will pave the way for development of novel pharmacological tools for the safe and better management of chronic pain in patients.