Cellular Tolerance Induced by Chronic Opioids in the Central Nervous System

Abstract

Opioids are powerful analgesics that elicit acute antinociceptive effects through their action the mu opioid receptor (MOR). However opioids are ineffective for chronic pain management, in part because continuous activation of MORs induces adaptive changes at the receptor level and downstream signaling molecules. These adaptations include a decrease in receptor-effector coupling and changes to second messenger systems that can counteract the persistent activation of MORs by opioid agonists. Homeostatic regulation of MORs and downstream signaling cascades are viewed as precursors to developing tolerance. However, despite numerous studies identifying crucial mechanisms that contribute to opioid tolerance, no single regulatory mechanism that governs tolerance in at the cellular and systems level has been identified. Opioid tolerance is a multifaceted process that involves both individual neurons that contain MORs and neuronal circuits that undergo adaptations following continuous MOR activation. The most proximal event is the agonist/receptor interaction leading to acute cellular actions. This review discusses our understanding of mechanisms that mediate cellular tolerance after chronic opioid treatment that, in part, is mediated by agonist/receptor interaction acutely.

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

“…64 Opioid receptors in the LC are implicated in pain, stress responses, and opioid side effects, namely, physical dependence and tolerance. 3,159 MOR is abundant at the LC 38 and opioids produce antinociception through presynaptic MOR-mediated inhibition of GABAergic neurons which disinhibits norepinephrine (NE) neurons projecting to the spinal cord. 134 Opioids also act through a postsynaptic mechanism hyperpolarizing NE neurons at the LC by activating GIRK channels.…”

“…85 Accordingly, specific enzymes responsible for receptor phosphorylation, such as the protein kinase C (PKC) and GRKs, have also been implicated in mediating opioid tolerance. 3 Neurons at the LC are particularly susceptible to desensitization on acute administration of opioids and develop tolerance after long-term treatment with opioids. 3 Studies on knockout mice expressing mutant versions of MOR established that the degree of phosphorylation of MOR at the carboxyl-terminal determines acute desensitization and long-term tolerance.…”

“…3 Neurons at the LC are particularly susceptible to desensitization on acute administration of opioids and develop tolerance after long-term treatment with opioids. 3 Studies on knockout mice expressing mutant versions of MOR established that the degree of phosphorylation of MOR at the carboxyl-terminal determines acute desensitization and long-term tolerance. 7 In addition, it seems that long-term treatment with morphine alters the regulation of GRK-mediated desensitization, in a manner that additional kinases are recruited contributing to desensitization in the LC.…”

Mu-opioid receptor and receptor tyrosine kinase crosstalk: Implications in mechanisms of opioid tolerance, reduced analgesia to neuropathic pain, dependence, and reward

“…As a result, escalation of opioid doses occurs over time to maintain analgesic benefit ( Henry et al, 2015 ; Hayhurst and Durieux, 2016 ). MOR signaling is essential in the mechanisms of tolerance ( Williams et al, 2013 ; Adhikary and Williams, 2022 ) and MOR is expressed in structures strongly implicated in tolerance and pain mechanisms including dorsal root ganglia (DRG) neurons and neurons of the spinal cord substantia gelatinosa ( Mansour et al, 1988 , 1995a ; Scherrer et al, 2009 ; Corder et al, 2017 ; Puig and Gutstein, 2017 ). RTKs are similarly expressed alongside MOR in the spinal cord and DRG, including PDGFRβ ( Sasahara et al, 1991 ; Eccleston et al, 1993 ), EGFR ( Werner et al, 1988 ; Huerta et al, 1996 ), VEGFR2 ( Spliet et al, 2004 ; Herrera et al, 2009 ), or Ephrin type-B receptor 1 (EphRB1) ( Liu et al, 2011 ).…”

“…Mechanisms of opioid analgesic tolerance and side-effects are still poorly understood ( Adhikary and Williams, 2022 ). Traditionally, tolerance was thought to occur via the direct modulation of MOR signaling and trafficking ( Williams et al, 2013 ).…”