The gut–brain interaction in opioid tolerance

Abstract

The prevailing opioid crisis has necessitated the need to understand mechanisms leading to addiction and tolerance, the major contributors to overdose and death and to develop strategies for developing drugs for pain treatment that lack abuse liability and side-effects. Opioids are commonly used for treatment of pain and symptoms of inflammatory bowel disease. The significant effect of opioids in the gut, both acute and chronic, include persistent constipation and paradoxically may also worsen pain symptoms. Recent work has suggested a significant role of the gastrointestinal microbiome in behavioral responses to opioids, including the development of tolerance to its pain-relieving effects. In this review, we present current concepts of gut-brain interaction in analgesic tolerance to opioids and suggest that peripheral mechanisms emanating from the gut can profoundly affect central control of opioid function.

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

“…Such an inhibition occurring within a clinically therapeutic range is not linked to agonistic or antagonistic effects on opioid receptors. Inasmuch as Na V channels play a role in neuropathic pain syndromes (Akbarali & Dewey, ; Catterall et al, ; Theile & Cummins, ), NAL‐mediated inhibition of I Na could be of clinical relevance (e.g., antinociceptive effect) (Barry & Zuo, ; Bindra et al, ; Chen et al, ; Davis et al, ; Withey et al, ). The modifications by NAL are thus important and lend credence to the notion that such actions are linked to their neurological or adverse actions (Bodnar, ; Candy, Jones, Vickerstaff, Larkin, & Stone, ; Dinges et al, ; Raghav et al, ).…”

“…3.3 | Comparison of the effects of NAL, NAL plus dynophin A 1-13 , and NAL plus naloxone on peak I Na NAL may interact with opioid receptors to modify ionic currents (e.g., I Na ) (Akbarali & Dewey, 2017;Fitting et al, 2015;Ross et al, 2012;Smith et al, 2012). The question arises as to whether the observed effects of NAL on I Na in mHippoE-14 neurons are linked to its binding to different types of opioid receptors.…”

“…Earlier studies have reported the expression of μ‐ or κ‐opioid receptors in hippocampal cells (Chen et al, ). How NAL can interact with these receptors to affect the amplitude or gating of ionic currents in hippocampal neurons remains unclear, although it was previously thought to bind to opioid receptors, thus modifying ionic currents in different types of cells (Akbarali & Dewey, ; Fitting et al, ; Ross et al, ; Smith et al, ).…”

The Microbiome and the Gut‐Liver‐Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models

“…An emerging literature describes a large contribution of peripheral tissues, both of the ENS in the gut and of the primary afferent relay neurons that transmit sensation from the gut to the spinal cord, whose cell bodies make up the dorsal root ganglion, in the modulation of pain and opioid responses. 71 Chronic opioid exposure activates toll-like receptors on epithelial cells of the gut, disrupting the gut epithelial barrier and allowing bacterial translocation. 72 As bacteria pass through, immune cells and enteric glia are activated and cytokines are released, setting in motion an inflammatory response cascade that is anti-analgesic and promotes worsening pain.…”

“…The μ opioid receptor interacts biochemically with adenylate cyclase, β-arrestin recruitment, and receptor phosphorylation by protein kinases C and A, and ERK 1/2. 71 Thus, not only does long-term opioid use cause a reduction in gut motility, we are now beginning to appreciate that it also plays a causal role in changes to the gut microbiota [79][80][81] that can, in turn, escalate inflammation in both the gut and CNS. 80,82 This effect of long-term opioid use on the gut microbiota also contributes to the physiologic changes that underlie addictive behavior, dysregulates immune response, and increases intestinal barrier permeability, bacterial translocation, the risk of enteric infection, morphine tolerance, and gut-derived sepsis.…”