Can we find chronic pain relief using repurposed drugs?
Unexpected pathways uncovered in pursuit of this pharma target.
Pain is a problem. BIG problem. It is a research topic pursued relentlessly, but to date, no silver bullet emerges. Yet, I comb the literature, looking for sprouts that may blossom into a potential solution. Recent found works utilize therapeutics that are already approved and commercially available. This newsletter will focus on those.
PROBENECID A gout drug
This uricosuric acts on renal tubular function and is used to increase the concentration of some drugs (such as penicillin) in the blood by inhibiting their excretion and to increase the excretion of urates in conditions such as gout. Researchers of membrane ATP-binding cassette (ABC) transporters use it as a standard inhibitor tool.
Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies. …
To explore the translational potential of our findings, we searched for FDA-approved inhibitors of OAT1 activity and found that the uricosuric drug Probenecid (PBN) is, at present, the sole OAT1 inhibitor suitable for clinical use (https://transportal.compbio.ucsf.edu/transporters/SLC22A6/#inhib). PBN is largely used in clinical practice for the treatment of gout and hyperuricemia. In terms of specificity, the IC50 of PBN for OAT1 is reported to be at least one order of magnitude smaller than for other potential targets. We delivered PBN or vehicle intrathecally to preferentially target OAT1 in the nervous system of inflamed mice. Compared to vehicle-treated inflamed mice, mice treated with PBN displayed significantly reduced CFA-triggered mechanical allodynia up to 24 h after a single intrathecal dose. PBN had no influence on basal mechanical responses or on the development of CFA-induced thermal hyperalgesia. Thus, PBN inhibits the development of CFA-triggered mechanical hypersensitivity but does not affect basal sensitivity. - C Litke et al.
FLUPHENAZINE An antipsychotic drug
Fluphenazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. It acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.
Neuropathic pain is a chronic condition for which effective safe treatments are lacking. Polymorphisms in the GTP cyclohydrolase 1 (GCH1) gene have been associated with chronic pain severity; and modulation of the GCH1/BH4 pathway has been shown to affect neuropathic pain. Here, Cronin et al. screened over a thousand annotated and FDA-approved compounds and showed that the antipsychotic fluphenazine hydrochloride reduced GCH1 expression and had analgesic effects in a neuropathic pain model in rodents. Among the hits, EGFR/KRAS pathway modulators also affected GCH1 expression, and the authors identified a common signaling, downstream KRAS, involving GCH1, that affects chronic pain and lung cancer development in mice. The results suggest that targeting this signaling could alleviate neuropathic pain.
ABSTRACT Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents. - S Cronin et al
The effective analgesic dose of fluphenazine in their experiments in the mouse model is comparable to the low end of the doses safely indicated for schizophrenia in humans.
CAFFEINE Our favorite daily drug
Once again, methylxanthines show us their magic.
The methylxanthine, caffeine, an adenosine receptor antagonist, is effective in reducing post operative pain. In particular, the rat model using surgical incision recovery, demonstrated that sleep deprivation increased pain measures. Caffeine was tested and found to be a reliever.
ABSTRACT Sleep and pain are reciprocally related, but the precise mechanisms underlying this relationship are poorly understood. This study used a rat model of surgical pain to examine the effect of previous sleep loss on postoperative pain and tested the hypothesis that preoptic adenosinergic mechanisms regulate sleep–pain interactions. Relative to ad libitum sleep, 6 hours of total sleep deprivation prior to a surgical incision significantly enhanced postoperative mechanical hypersensitivity in the affected paw and prolonged the time to recovery from surgery. There were no sex-specific differences in these measures. There were also no changes in adrenocorticotropic hormone and corticosterone levels after sleep deprivation, suggesting that this effect was not mediated by the stress associated with the sleep perturbation. Systemic administration of the nonselective adenosine receptor antagonist caffeine at the onset of sleep deprivation prevented the sleep deprivation-induced increase in postoperative hypersensitivity. Microinjection of the adenosine A2A receptor antagonist ZM 241385 into the median preoptic nucleus (MnPO) blocked the increase in surgical pain levels and duration caused by prior sleep deprivation and eliminated the thermal hyperalgesia induced by sleep deprivation in a group of nonoperated (i.e., without surgical incision) rats. These data show that even a brief sleep disturbance prior to surgery worsens postoperative pain and are consistent with our hypothesis that adenosine A2A receptors in the MnPO contribute to regulate these sleep–pain interactions. - VS Hambrecht-Wiedbusch et al.
Ahhhhh…
deep peaceful blissful sleep is the most effective painkiller of them all.
REFERENCES
C Litke et al. Organic anion transporter 1 is an HDAC4-regulated mediator of nociceptive hypersensitivity in mice. Nature Communications (2022). DOI: 10.1038/s41467-022-28357-x
S Cronin et al. Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer, Science Translational Medicine (2022). www.science.org/doi/10.1126/scitranslmed.abj1531. https://www.science.org/doi/10.1126/scitranslmed.abj1531
Old drugs hint at new ways to beat chronic pain (2022, August 31) https://medicalxpress.com/news/2022-08-drugs-hint-ways-chronic-pain.html
VS Hambrecht-Wiedbusch et al. Preemptive Caffeine Administration Blocks the Increase in Postoperative Pain Caused by Previous Sleep Loss in the Rat: A Potential Role for Preoptic Adenosine A2A Receptors in Sleep–Pain Interactions, Sleep (2017). DOI: 10.1093/sleep/zsx116
I do a decent amount of integrative pain management. My school of thought is that you normally have to identify the pain generator and treat it, but the nature of the pain generator is often such that it lies outside a conventional model and hence cannot be treated within that paradigm (e.g. I think Neural Therapy is amazing but most docs won't touch it).
The two holistic therapies I've found are often quite effective in treating pain that appear relatively safe and do not require knowing the specific pain generator are using DMSO or Wild Lettuce (an herb that is an adenosine agonist--which is what opioid receptors end up doing as well).