Recent advances in developing opioid treatments for pain with reduced side effects have focused on the signaling cascades of the μ-opioid receptor (MOR). However, few such signaling targets have been identified for exploitation. To address this need, we explored the role of heat-shock protein 90 (Hsp90) in opioid-induced MOR signaling and pain, which has only been studied in four previous articles. First, in four cell models of MOR signaling, we found that Hsp90 inhibition for 24 h with the inhibitor 17--allylamino-17-demethoxygeldanamycin (17-AAG) had different effects on protein expression and opioid signaling in each line, suggesting that cell models may not be reliable for predicting pharmacology with this protein. We thus developed an model using CD-1 mice with an intracerebroventricular injection of 17-AAG for 24 h. We found that Hsp90 inhibition strongly blocked morphine-induced anti-nociception in models of post-surgical and HIV neuropathic pain but only slightly blocked anti-nociception in a naive tail-flick model, while enhancing morphine-induced precipitated withdrawal. Seeking a mechanism for these changes, we found that Hsp90 inhibition blocks ERK MAPK activation in the periaqueductal gray and caudal brain stem. We tested these signaling changes by inhibiting ERK in the above-mentioned pain models and found that ERK inhibition could account for all of the changes in anti-nociception induced by Hsp90 inhibition. Taken together, these findings suggest that Hsp90 promotes opioid-induced anti-nociception by an ERK mechanism in mouse brain and that Hsp90 could be a future target for improving the therapeutic index of opioid drugs.

The therapeutic index (TI) inversely varied as a function of amount of SNC80 in the mixture, such that lower amounts of SNC80 produced a higher TI, and larger amounts produced a lower TI. Compared to literature using standard pain-elicited assays, the orderly relationship between SNC80 and TI reported here may be a unique function of assessing pain-depressed behavior.

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Given the reported effects of gut microbiome modulation on local gut inflammation and intestinal pain, it is possible that gut microbiota regulate persistent or chronic pain conditions that are distal to the gut, including pain states in the extremities. This study evaluated the effects of gut microbiome modulation on formalin pain‐depressed behaviors and formalin‐induced paw inflammation in female Fisher rats. Pilot data indicate that (1) a two‐week regimen of the narrow‐spectrum gram‐positive antibiotic vancomycin (500mg/L) in drinking water depleted Firmicutes and Bacteroidetes diversity / density in rats with or without access to running wheels; (2) formalin alone (0.5, 2.5, 5%) produced concentration‐dependent biphasic licking behavior of injured hind paw across 60 min and concentration‐dependent depression of voluntary wheel running for 7 consecutive days; (3) two‐week antibiotic treatment prior to formalin administration had a protective effect manifested as attenuation of Phase II formalin scores, and complete reversal of formalin pain‐depressed wheel running for 7 consecutive days; (4) the protective effects of vancomycin on formalin pain‐related outcomes were associated with divergent changes to proteobacteria in sedentary vs. voluntary exercised rats. These data indicate that a narrow spectrum gram‐positive antibiotic can have lasting protective effects on persistent pain‐related behaviors and that associated changes to gut microbiota vary as a function of sedentary vs. exercise condition. Parallel mechanistic studies are currently assessing the efficacy of probiotic and fecal microbiota transplant procedures vs. opioid compounds to block antibiotic‐induced modulation to formalin pain‐related outcomes.Support or Funding InformationThis research supported by a NIH COBRE grant (P20GM103643) that supports an animal behavior core facility, and a COBRE Pilot award and NIAMS R15 AREA grant (AR054975) to G.W.S.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.