Narrative review of the scientific and methodological explanations for 101 mechanisms of opioid tolerance

Opioids such as morphine and fentanyl are widely prescribed treatments for pain. Unfortunately, opioid use is limited by side effects, dependence, and the development of tolerance with repeated use. A major goal of preclinical opioid research is to identify the neural mechanisms underlying tolerance to opioids to provide better pain management and reduce side effects caused by high opioid doses. To that end, preclinical pain researchers have reported well over 101 mechanisms of opioid tolerance. The objective of this review is to describe both the scientific explanations for multiple mechanisms of opioid tolerance (eg, different types of opioid tolerance, different mechanisms at different locations and for different opioids) and the methodological problems that cause false positives. For example, many changes correlate with but do not cause tolerance. Opioid binding to mu-opioid receptors (MOR) activates a signaling cascade that includes numerous molecules and cells making it difficult to identify the precise mechanism causing tolerance. Other problems, such as lack of appropriate control groups or confounds produced by antinociceptive or motor effects of the treatment, are surprisingly common. Solutions to these problems are presented at the end of the article in the hope of guiding future research. Although the focus is on opioid tolerance, the problems and solutions presented here apply to tolerance to other drugs and any neural change that occurs over time such as learning.