Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models

Stine, Carrie; Coleman, Deziree L; Flohrschutz, Austin; Thompson, Austen; Mishra, Satyendra; Blagg, Brian S. J.; W, Lei; Streicher, John M.

doi:10.1097/j.pain.0000000000001886

Cited by 14 publications

(20 citation statements)

References 43 publications

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“…Mechanical allodynia was measured using calibrated von Frey filaments by the up-down method as in the literature and our previous work. 3,25,46 Baselines were recorded on day 0 before paclitaxel and on day 8 before drug injection; all animals demonstrated mechanical allodynia after paclitaxel treatment, so none were excluded from the study. Details on drug injections are provided in the figure legends, and allodynia was measured over a time course postinjection.…”

Section: Chemotherapy-induced Peripheral Neuropathymentioning

confidence: 99%

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Keresztes

Olson

Nguyen

et al. 2021

Pain

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The opioid receptors are important regulators of pain, reward, and addiction. Limited evidence suggests the mu and delta opioid receptors form a heterodimer (MDOR), which may act as a negative feedback brake on opioid-induced analgesia. However, evidence for the MDOR in vivo is indirect and limited, and there are few selective tools available. We recently published the first MDOR-selective antagonist, D24M, allowing us to test the role of the MDOR in mice. We thus cotreated CD-1 mice with D24M and opioids in tail flick, paw incision, and chemotherapy-induced peripheral neuropathy pain models. D24M treatment enhanced oxymorphone antinociception in all models by 54.7% to 628%. This enhancement could not be replicated with the mu and delta selective antagonists CTAP, naltrindole, and naloxonazine, and D24M had a mild transient effect in the rotarod test, suggesting this increase is selective to the MDOR. However, D24M had no effect on morphine or buprenorphine, suggesting that only specific opioids interact with the MDOR. To find a mechanism, we performed phosphoproteomic analysis on brainstems of mice. We found that the kinases Src and CaMKII were repressed by oxymorphone, which was restored by D24M. We were able to confirm the role of Src and CaMKII in D24M-enhanced antinociception using small molecule inhibitors (KN93 and Src-I1). Together, these results provide direct in vivo evidence that the MDOR acts as an opioid negative feedback brake, which occurs through the repression of Src and CaMKII signal transduction. These results further suggest that MDOR antagonism could be a means to improve clinical opioid therapy.

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Section: Chemotherapy-induced Peripheral Neuropathymentioning

confidence: 99%

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Keresztes

Olson

Nguyen

et al. 2021

Pain

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“…Further factors argue for the clinical potential of our findings. Our earlier work suggests that other opioids, specifically oxymorphone, are regulated similarly by Hsp90 inhibition as morphine, albeit in different pain models and inhibitor route [15]. This suggests that a broad spectrum of opioid drugs could be improved.…”

Section: Discussionmentioning

confidence: 99%

“…We tested this using male and female CD-1 mice injected with 0.01 nmol of the non-isoform-selective Hsp90 inhibitor KU-32 or Vehicle control by the i.t. route with a default treatment time of 24 hours (time point based on our earlier work [13][14][15][16]). After the 24 hour treatment time, the mice were treated with a dose range of morphine and antinociception was measured.…”

Section: Spinal Hsp90 Inhibition Enhances Morphine Anti-nociception I...mentioning

confidence: 99%

“…In our work, we've uncovered a role for Hsp90 in opioid signaling and anti-nociception that differs between the brain and spinal cord. In brain, Hsp90 promotes ERK MAPK signaling via the Hsp90α isoform and the cochaperones Cdc37 and p23; Hsp90 inhibitor treatment in the brain thus reduces ERK MAPK signaling and opioid anti-nociception [13][14][15]. In contrast, Hsp90 represses opioid anti-nociception and signaling in the spinal cord, so that Hsp90 inhibitor treatment in the spinal cord promotes an ERK-RSK signaling cascade that results in enhanced opioid anti-nociception [16].This enhanced anti-nociception led us to hypothesize that spinal Hsp90 inhibitor treatment could be used to improve the therapeutic index of opioids and enable a dose-reduction strategy.…”

mentioning

confidence: 99%

“…ICR) mice are commonly used in opioid research as a line with a strong response to opioid drugs (e.g. [24], and our own previous Hsp90 research [13][14][15][16]). Mice were recovered for a minimum of 5 days after shipment before being used in experiments.…”

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Inhibiting Spinal Cord-Specific Hsp90 Isoforms Reveals a Novel Strategy to Improve the Therapeutic Index of Opioid Treatment

et al. 2021

Preprint

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Opioid drugs are the gold standard for treating acute and chronic pain, but are limited by negative side effects, including tolerance, constipation, and addiction. New approaches are thus greatly needed to improve opioid therapy and decrease side effects. Our investigations have revealed Heat shock protein 90 (Hsp90) as a critical regulator of opioid receptor signaling, and that inhibition of spinal cord Hsp90 boosts opioid anti-nociception. These findings led us to hypothesize that spinal Hsp90 inhibitor treatment could improve the therapeutic index of opioids, boosting anti-nociception while improving or not altering side effects, enabling a dose-reduction strategy. To test this hypothesis, we injected the Hsp90 inhibitor KU-32 by the intrathecal route into male and female CD-1 mice. We then tested these mice for their response to morphine in a battery of anti-nociception and side effect models. We found that spinal KU-32 treatment increased the anti-nociceptive potency of morphine by 2-4 fold in the tail flick, post-surgical paw incision, and HIV peripheral neuropathy pain models. At the same time, morphine anti-nociceptive tolerance was reduced from 21 fold to 2.9 fold by KU-32 treatment, and established morphine tolerance could be rescued by KU-32 injection. Reward as measured by conditioned place preference and constipation were both unchanged. These results support our hypothesis, and suggest that Hsp90 inhibitors could be a novel approach to improve the therapeutic index of opioids, enable a dose-reduction strategy, and lead to fewer side effects during pain therapy.

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Modelling skeletal pain harnessing tissue engineering

et al. 2022

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Bone pain typically occurs immediately following skeletal damage with mechanical distortion or rupture of nociceptive fibres. The pain mechanism is also associated with chronic pain conditions where the healing process is impaired. Any load impacting on the area of the fractured bone will stimulate the nociceptive response, necessitating rapid clinical intervention to relieve pain associated with the bone damage and appropriate mitigation of any processes involved with the loss of bone mass, muscle, and mobility and to prevent death. The following review has examined the mechanisms of pain associated with trauma or cancer-related skeletal damage focusing on new approaches for the development of innovative therapeutic interventions. In particular, the review highlights tissue engineering approaches that offer considerable promise in the application of functional biomimetic fabrication of bone and nerve tissues. The strategic combination of bone and nerve tissue engineered models provides significant potential to develop a new class of in vitro platforms, capable of replacing in vivo models and testing the safety and efficacy of novel drug treatments aimed at the resolution of bone-associated pain. To date, the field of bone pain research has centred on animal models, with a paucity of data correlating to the human physiological response. This review explores the evident gap in pain drug development research and suggests a step change in approach to harness tissue engineering technologies to recapitulate the complex pathophysiological environment of the damaged bone tissue enabling evaluation of the associated pain-mimicking mechanism with significant therapeutic potential therein for improved patient quality of life. Graphical abstract Rationale underlying novel drug testing platform development. Pain detected by the central nervous system and following bone fracture cannot be treated or exclusively alleviated using standardised methods. The pain mechanism and specificity/efficacy of pain reduction drugs remain poorly understood. In vivo and ex vivo models are not yet able to recapitulate the various pain events associated with skeletal damage. In vitro models are currently limited by their inability to fully mimic the complex physiological mechanisms at play between nervous and skeletal tissue and any disruption in pathological states. Robust innovative tissue engineering models are needed to better understand pain events and to investigate therapeutic regimes

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Heat shock protein 90 inhibitors block the antinociceptive effects of opioids in mouse chemotherapy-induced neuropathy and cancer bone pain models

Cited by 14 publications

References 43 publications

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Antagonism of the mu-delta opioid receptor heterodimer enhances opioid antinociception by activating Src and calcium/calmodulin-dependent protein kinase II signaling

Inhibiting Spinal Cord-Specific Hsp90 Isoforms Reveals a Novel Strategy to Improve the Therapeutic Index of Opioid Treatment

Modelling skeletal pain harnessing tissue engineering

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