Pain Management: A promising alternative to opioids
A complex extracted from the amniotic membrane in humans reduces post-surgical pain in mice by directly inhibiting pain-sensing neurons.
- Department of Pain Management, Cleveland Clinic, United States
- Department of Neuroscience, Cleveland Clinic, United States
Post-surgical pain affects millions of people every year, and managing it is a critical aspect of patient care (Tait et al., 2018). Effective pain relief is essential both for comfort and also for preventing complications such as chronic pain or delayed recovery.
Traditionally, a broad group of pain-relieving medicines known as opioids have been the cornerstone of post-surgical pain treatment. By binding to pain receptors, opioids reduce pain intensity. However, opioids can cause nausea, constipation and respiratory depression, and they also have the potential to be addictive (Stein, 2016). Indeed, their widespread use is believed to have contributed to an opioid epidemic that has resulted in high rates of addiction, overdose and death, particularly in the United States (Hornberger and Chhatwal, 2021; The Lancet., 2021). This underscores the need for alternative pain management strategies that can effectively control pain without causing dangerous side effects.
For decades, the amniotic membrane – the innermost layer of the placenta – has been used to heal wounds and to repair damage to the surface of the eye through its anti-inflammatory and anti-scarring properties (Díaz-Prado et al., 2011; Law et al., 2022). Now, in eLife, Yun Guan and Shao-Qui He of Johns Hopkins University and colleagues – including Chi Zhang, Qian Huang, and Neil Ford as joint first authors – report that a human amniotic membrane product shows promise as an opioid alternative for post-surgical pain management (Zhang et al., 2024).
Clarix Flo (or FLO for short) contains a rich matrix of biologically active molecules derived from the amniotic membrane that can modulate cellular activity. To investigate whether FLO can reduce post-surgical pain, Zhang et al. applied it to surgical sites in mice, finding that this significantly reduced sensitivity to post-surgical pain. This effect was shown to depend on CD44, a cell surface receptor that is involved in various physiological and pathological processes. By interacting with the CD44 receptor, FLO inhibits the activity of specialized sensory neurons located in the dorsal root ganglia that are responsible for transmitting pain signals to the central nervous system. This means that FLO targets pain signaling at its source, which is markedly different from how opioids work.
To identify the component within FLO responsible for this effect, the team isolated a complex known as HC-HA/PTX3, which is found in uniquely high amounts in birth tissues. Applying this complex alone replicated the pain-inhibiting effects of FLO. HC-HA/PTX3 was also purer than FLO and more soluble in water, which increases its therapeutic potential by making it less likely to cause adverse effects and more likely to reach its target site. Further experiments revealed that HC-HA/PTX3 induces cytoskeletal rearrangements in pain-sensing neurons. This inhibits critical sodium and high-voltage calcium currents that are vital for propagating pain signals, significantly reducing the ability of these neurons to transmit pain signals to the central nervous system (Figure 1).
Figure 1
Targeting pain signaling at its source.
(A) Painful stimuli are detected through a process called nociception. Neurons (orange) located in the dorsal root ganglia (DRG) relay pain signals from a peripheral wound (such as a skin injury; left) to the central nervous system (right), which results in pain being experienced. (B) After surgery, sodium ions (Na+; green) and calcium ions (Ca2+; blue) flow into DRG nociceptive neurons through ion channels (pink) that are embedded in the cell wall of the neurons. This contributes to acute post-surgical pain. (C) HC-HA/PTX3 or FLO (dark green shapes) can bind to CD44 receptors (red lines) on the surface of the DRG neurons. This binding leads to a rearrangement of the cytoskeleton within the cell, which pushes the receptors into the neuron, causing some of the ion channels to close. The resulting reduction in the influx of sodium and calcium ions leads to a decrease in pain signaling. This figure was created using BioRender.com.
The discovery that HC-HA/PTX3 is the key bioactive component in FLO makes it a potential candidate for acute post-surgical and chronic pain management in various clinical settings. While this opens exciting avenues for future research, before HC-HA/PTX3 can be fully translated from preclinical research to clinical application, important questions must be answered. One key challenge is determining whether the effects observed in mice translate to human patients. Although pain signaling pathways are largely conserved across species, human clinical trials are necessary to confirm the efficacy and safety of HC-HA/PTX3. Researchers are also considering whether combining the complex with other non-opioid treatments, such as anti-inflammatory drugs or nerve growth inhibitors, could create a more comprehensive approach to pain management.
Despite these uncertainties, the findings of Zhang et al. represent a significant step forward in the search for effective, non-opioid pain therapies. By targeting the underlying pain mechanisms at the cellular level, rather than simply masking the symptoms as opioids do, biologically derived products like HC-HA/PTX3 could revolutionize post-surgical and chronic pain treatment. While much work remains to bring these discoveries to clinical practice, the promise of safer, more effective pain management is an exciting prospect in the ongoing fight against the opioid epidemic.
References
-
Opioid misuse: A global crisisValue in Health 24:145–146.https://doi.org/10.1016/j.jval.2020.12.003
-
Opioid ReceptorsAnnual Review of Medicine 67:433–451.https://doi.org/10.1146/annurev-med-062613-093100
-
Persistent post-mastectomy pain: Risk factors and current approaches to treatmentThe Journal of Pain 19:1367–1383.https://doi.org/10.1016/j.jpain.2018.06.002
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© 2024, Zhang and Cheng
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Pain Management: A promising alternative to opioids
eLife 13:e103003.
https://doi.org/10.7554/eLife.103003
Further reading
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- Medicine
Gremlin-1 has been implicated in liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH) via inhibition of bone morphogenetic protein (BMP) signalling and has thereby been identified as a potential therapeutic target. Using rat in vivo and human in vitro and ex vivo model systems of MASH fibrosis, we show that neutralisation of Gremlin-1 activity with monoclonal therapeutic antibodies does not reduce liver inflammation or liver fibrosis. Still, Gremlin-1 was upregulated in human and rat MASH fibrosis, but expression was restricted to a small subpopulation of COL3A1/THY1+ myofibroblasts. Lentiviral overexpression of Gremlin-1 in LX-2 cells and primary hepatic stellate cells led to changes in BMP-related gene expression, which did not translate to increased fibrogenesis. Furthermore, we show that Gremlin-1 binds to heparin with high affinity, which prevents Gremlin-1 from entering systemic circulation, prohibiting Gremlin-1-mediated organ crosstalk. Overall, our findings suggest a redundant role for Gremlin-1 in the pathogenesis of liver fibrosis, which is unamenable to therapeutic targeting.
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- Medicine
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Background:
Chemotherapy-induced peripheral neuropathy (CIPN) is a serious therapy-limiting side effect of commonly used anticancer drugs. Previous studies suggest that lipids may play a role in CIPN. Therefore, the present study aimed to identify the particular types of lipids that are regulated as a consequence of paclitaxel administration and may be associated with the occurrence of post-therapeutic neuropathy.
Methods:
High-resolution mass spectrometry lipidomics was applied to quantify d=255 different lipid mediators in the blood of n=31 patients drawn before and after paclitaxel therapy for breast cancer treatment. A variety of supervised statistical and machine-learning methods was applied to identify lipids that were regulated during paclitaxel therapy or differed among patients with and without post-therapeutic neuropathy.
Results:
Twenty-seven lipids were identified that carried relevant information to train machine learning algorithms to identify, in new cases, whether a blood sample was drawn before or after paclitaxel therapy with a median balanced accuracy of up to 90%. One of the top hits, sphinganine-1-phosphate (SA1P), was found to induce calcium transients in sensory neurons via the transient receptor potential vanilloid 1 (TRPV1) channel and sphingosine-1-phosphate receptors.SA1P also showed different blood concentrations between patients with and without neuropathy.
Conclusions:
Present findings suggest a role for sphinganine-1-phosphate in paclitaxel-induced biological changes associated with neuropathic side effects. The identified SA1P, through its receptors, may provide a potential drug target for co-therapy with paclitaxel to reduce one of its major and therapy-limiting side effects.
Funding:
This work was supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG, Grants SFB1039 A09 and Z01) and by the Fraunhofer Foundation Project: Neuropathic Pain as well as the Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD). This work was also supported by the Leistungszentrum Innovative Therapeutics (TheraNova) funded by the Fraunhofer Society and the Hessian Ministry of Science and Arts. Jörn Lötsch was supported by the Deutsche Forschungsgemeinschaft (DFG LO 612/16-1).
