Underpinning the Neurobiological Intricacies Associated with Opioid Tolerance

Abstract

The opioid crisis is a major threat of the 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 therapy for the management of chronic pain in clinics. The reason behind this is the development of potential side effects and tolerance after repeated dosing. Opioid tolerance is the major limiting factor leading to the withdrawal of treatment, severe side effects due to dose escalation, and sometimes even death of the patients. Every day more than 90 people die due to opioids overdose in America, and a similar trend has been seen across the globe. Over the past two decades, researchers have been trying to dissect the neurobiological mechanism of opioid tolerance. Research on opioid tolerance shifted toward central nervous system-based adaptations because tolerance is much more than just a cellular phenomenon. Thus, neurobiological adaptations associated with opioid tolerance are important to understand in order to find newer pain therapeutics. These adaptations are associated with 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 focused on novel circuitries associated with opioid tolerance in different areas of the brain, such as periaqueductal gray, rostral ventromedial medulla, dorsal raphe nucleus, ventral tegmental area, and nucleus accumbens. Understanding the neurobiological modulations associated with chronic opioid exposure and tolerance will pave the way for the development of novel pharmacological tools for safer and better management of chronic pain in patients.

Molecular mechanisms of opioid tolerance: From opioid receptors to inflammatory mediators (Review)

“…Although it has been widely established that opioid drugs are critical to proper pain management and that their receptor desensitisation is closely associated with opioid tolerance, the role of inflammation and the associated molecular mechanisms in this phenomenon have not been well studied until relatively recently ( 13 ). A growing body of literature suggests that activated microglia and astrocytes (glia) are the primary targets in pain management, because of their function in pain transmission and opioid analgesia ( 14 , 15 ).…”

Multifarious Targets and Recent Developments in the Therapeutics for the Management of Bone Cancer Pain

“…Opioids are frequently used for moderate to severe pain state, but they are associated with several toxic side effects which include respiratory depression, nausea and vomiting, constipation, sedation, and cognitive deficits . Eventually, addiction and tolerance that develop with prolonged opioid use led to the fall of opioids from the first line to the second and third line treatment options . It was also observed that opioid use is increasing the likelihood of bone destruction and tumor growth in BCP condition, giving all the more reason to avoid treatment with opioids .…”

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

“…For examination of peripheral analgesia, studies have shed light on the peripheral analgesic tolerance [68,69]. Research on the development of the centrally mediated opioid analgesic tolerance and related mechanisms has been reviewed extensively elsewhere [20,23,[70][71][72]. Available evidence related to peripheral analgesia and analgesic tolerance is summarized below.…”