The “Culture” of Pain Control: A Review of Opioid-Induced Dysbiosis (OID) in Antinociceptive Tolerance

Abstract

It is increasingly recognized that chronic opioid use leads to maladaptive changes in the composition and localization of gut bacteria. Recently, this "opioid-induced dysbiosis" (OID) has been linked to antinociceptive tolerance development in preclinical models and may therefore identify promising targets for new opioid-sparing strategies. Such developments are critical to curb dose escalations in the clinical setting and combat the ongoing opioid epidemic. In this article, we review the existing literature that pertains to OID, including the current evidence regarding its qualitative nature, influence on antinociceptive tolerance, and future prospects. Perspective: This article reviews the current literature on OID of gut bacteria, including its qualitative nature, influence on antinociceptive tolerance, and future prospects. This work may help identify targets for new opioid-sparing strategies.

Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic voluntary morphine

“…One could envision that the timing of its higher abundance could prime the mucosa and microbiota to resist some aspects of dysbiosis and did so better than native Lactobacillus and Bifidobacterium, which were elevated in tolerant mice pre-morphine (Figure 4B). In accordance with this, vancomycin pre-treatment, which substantially enriches for A. muciniphila 203,204 , curtails tolerance in vivo in mice and in vitro in neurons even without decreasing microbiota abundance-an affect suggested to be due to the concurrent general decrease in gram positive bacteria, many of which are mutualistic and produce butyrate 38,106,188 . Incidentally, vancomycin also improves aspects of autism spectrum disorder, a condition that correlates with low abundance of A. muciniphila 205 , and with low SCFA production 206 .…”

“…The replication of protection from tolerance by diet supplementation of butyrate alone (Figure 6) suggests a mechanism by which the identified taxa could exert their effects and could explain why differential loss of such community members could lead to cytokine-directed inflammation that is a suggested cause of opioid-induced hyperalgesia and tolerance 19,38,41,175 (Supplemental Figure 14), though it does not dictate that other mechanisms are not at play. One possibility is that butyrate palliatively countered the reduced analgesic benefits of morphine as tolerance developed by changing the threshold of pain perception by attenuating inflammation, thereby preventing pain sensitization of nociceptor neurons, rather than preventing homeostatic adaptations from occurring 41,188 (Figure 7; Supplemental Figure 14). This aligns with a recent study showing butyrate protection from hyperalgesia 47 .…”

Pain and Opioid-Induced Gut Microbial Dysbiosis

“…Many have documented a link between dysbiosis and analgesic tolerance through pro-inflammatory signalling pathways [ 79 ]. Recent findings imply the significance of pain pathways in contributing to tolerance, with evidence suggesting the involvement of primary afferent neurons [ 80 , 81 ]. Further research into the specific role of the microorganisms associated with OID will improve understanding of the correlation between these processes and antinociceptive tolerance and aid the development of novel treatments.…”

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

“…This section provides a brief overview of opioid-induced dysbiosis and the data supporting the concept that microbial alterations contribute to analgesic tolerance. Notably, a detailed review by Mischel and co-workers [132] has been recently published, to which the reader is referred for further information and more extensive bibliography.…”