Short-chain fatty acid, butyrate prevents morphine-and paclitaxel-induced nociceptive hypersensitivity

Abstract

Nociceptive hypersensitivity is a significant side effect with the chronic administration of opioids as well as chemotherapeutics. Both opioid-induced hypersensitivity (OIH) and chemotherapy-induced hypersensitivity (CIH) are characterized by an increased sensitivity to painful stimuli which can significantly reduce the quality of life for individuals on either drug(s). Here we demonstrate the nociceptive hypersensitivity associated with repeated administration of morphine (opioid) and paclitaxel (chemotherapeutic) treatment can be reversed by oral supplementation with the short-chain fatty acid (SCFA) sodium butyrate (NaBut). In two separate mouse behavioral models for nociceptive hypersensitivity, we found that thermal hyperalgesia (for OIH) and cold allodynia (for CIH) were prevented by treatment with oral butyrate (p.o, b.i.d). Electrophysiological recordings of small diameter dorsal root ganglia (DRG) neurons from morphine and paclitaxel treated mice showed an increase in neuronal hyperexcitability in both drug models which was likewise prevented by oral butyrate treatment. Using colonic conditioned media obtained from excised colon segments we found that gut mediators of morphine treated mice can induce hyperexcitability in naïve DRG neurons, but such enhanced excitability is not present when animals are co-treated with NaBut suggesting gut derived mediators modulate neuronal hyperexcitability. In-vitro NaBut treatment did not prevent morphine-induced excitability, suggesting an indirect role of butyrate in modulating neuronal hypersensitivity. These data taken together suggest that gut derived mediators affect opioid and chemotherapeutic-induced neuronal hypersensitivity that is prevented by the SCFA butyrate.

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 morphine

“…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 . However, the development of tolerance in our paradigm did not require hyperalgesia (Supplemental Figure 4; Supplemental Figure 13C, D), and four mice with naturally lower levels of some butyrate producers (e.g.…”

“…Butyrate could change the course/severity of the homeostatic adaptations in neurons thought to underlie tolerance and/or hyperalgesia associated with chronic morphine administration (Figure 7). In support of a direct role of butyrate on neuronal excitability, co-administration of butyrate in morphine-treated mice prevents morphine-induced changes in excitability of opioid receptor expressing neurons in the DRG 47 thought to underlie hyperalgesia. In addition, as a ligand for two of its receptors, including the free-fatty acid receptor 3 (FFAR3) and GPR109A, which, like MOR, are Gi-coupled receptors, butyrate could mask either inflammatory-mediated or non-inflammatory mediated hyperexcitability by providing Gi signaling (Figure 7).…”

“…The mice in our study underwent modest morphine treatment protocols that produced tolerance without significant hyperalgesia, and, as such, butyrate was protective for this tolerance even in the absence of hyperalgesia (Supplemental Figure 2; Supplemental Figure 13C,D). Hence, butyrate supplementation could be a useful tool for experimentally identifying and uncoupling parallel mechanisms that contribute to antinociceptive tolerance 47 (Figure 7, Supplemental Figure 14).…”

“…Through their activation of MORs in the gastrointestinal tract, opioids impair motility and secretion 36,37 and alter the gut microbiota 12,[38][39][40][41][42][43] . Gut microbiota dysbiosis is implicated in opioid-induced changes in drug reward 43,44 , dependence 40,45,46 , hyperalgesia 43,47 , and analgesic tolerance 19,38,41 . Several studies document that morphine-induced gut microbiota dysbiosis and subsequent translocation of pathobionts across a morphine-compromised gut barrier trigger inflammation that exacerbates the development of tolerance 27,35,41,48 (Supplemental Figure 2).…”

The role of morphine‐ and fentanyl‐induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota‐gut‐brain axis

“…Consequently, these results indicated that improving the intestinal epithelial barrier function prevented the development of tolerance to opioid‐induced antinociception. These findings add to the growing body of evidence of the role of the gut in mediating substance use disorders 64–66 . Although SCFAs can cross the blood–brain barrier, approximately 95% of orally administered butyrate is absorbed locally in the intestine and extremely low concentrations of oral butyrate are detected in systemic circulation or brain 67–69 .…”