Katarzyna Popiołek - Barczyk, PhD
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Decoding the novel role of the histamine H3 receptor in opioid-induced analgesia and hyperalgesia: studies toward innovative therapies for chronic pain - 2025-11-26 - 2029-11-25
Chronic pain is a major health issue in the global population that clearly impacts the individuals’ health status and quality of life and represents a major clinical, social, and economic problem. In the European Union, €300 billion per year was spent on the treatment of chronic pain. The studies affirmed that pain and pain-related diseases are the leading cause of disability globally. Neuropathic pain is a pathological disorder caused by lesions or diseases of the somatosensory nervous system, where pain loses its protective and adaptative function and paradoxically leads to increased pain sensitivity. To date, no drug has shown long‐term efficacy, and this type of pain is recognized to be particularly difficult to treat. Epidemiological data revealed that neuropathic pain is prevalent in 6.9-10% of the general population, affecting more women (8%) than men (5.7%). Despite greatly improving our understanding of this pathology, 40% of patients did not achieve satisfactory pain relief. Therefore, pharmacological therapies are considered to constitute an unmet medical need.
Despite advancements in understanding neuropathic pain mechanisms, effective long-term therapies remain elusive, with opioids continuing to dominate despite severe side effects, among which are opioid-induced hyperalgesia (OIH), tolerance, respiratory depression, hyperlocomotion, central sleep apnea, which are of major importance. OIH is a state of enhanced nociception observed upon opioid administration, which is a troublesome clinical issue with a still unknown mechanism. The poorly controlled chronic pain results in the escalation of opioids used. Data from recent years highlights the increased risk of overdose death associated with opioid-based pain therapy. However, the situation is even more alarming during the time of pandemic COVID-19, when the increase in opioid overdose was attributed to reduced access to the healthcare system. Moreover, with potentially fatal consequences, opioid-related side effects may limit the use of opioid analgesia, resulting in inadequate pain treatment. Therefore, development in this area is crucial for understanding the mechanism of the opioid switch from analgesic medication to hyperalgesic ”medication” with harmful side effects.
Our recent studies indicate that histamine 3 receptor (H3R) is a promising target for research into new analgesic drugs in neuropathic pain therapy. We revealed that H3R antagonists have a strong analgesic effect, and interestingly, the blockade of H3R produced prolonged pain relief in neuropathic females. Moreover, our pharmacological studies demonstrated that H3R antagonist potentiated morphine analgesia. Our data strongly suggest that drugs acting at different molecular targets and by different mechanisms may help to reduce opioid doses and, in consequence, limit opioid dose escalation. This pharmacological approach, when lower doses of drugs are used, results in fewer side effects and provides a promising further pharmacological intervention in neuropathic pain and OIH. Our preliminary data have shown that the clinically used drug pitolisant produced strong analgesic effects in neuropathic mice and reduced morphine-induced hyperlocomotion. Pitolisant (Wakix®, Ozawade®) is the first marketed H3R antagonist, use in human therapy for adults suffering from narcolepsy and Obstructive Sleep Apnoea. In 2023, pitolisant received its first approval in adolescents and children to treat Excessive Daytime Sleepiness in the EU. Pitolisant is a substance of great therapeutic potential but is currently very understudied in the context of chronic pain and opioid analgesia. Unlike previous strategies, our approach leverages to combine pitolisant, which is already in a clinic with a favorable safety profile, with morphine, a gold-standard opioid analgesic. Therefore, our project has a translational character and might have a great chance of being included in human therapy. Using a comprehensive approach, combining behavioral tests with electrophysiological studies and novel molecular techniques (such as Imaging Mass Cytometry and data-independent acquisition (DIA) quantitative proteomic analysis), we will bridge the gap in the H3R molecular mechanism of action in neuropathic pain and OIH development. Another novel approach to our project is to investigate the sex-related differences in H3R antagonists actions in the course of opioid analgesia and hyperalgesia, which remained a fully unexplored issue. We believe that obtaining unique results will enrich our knowledge and establish a basis for a new approach to enhancing the utility of opioids in treating chronic pain.
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Pharmacological modulation of histamine H3 and H4 receptors - a new perspective in the treatment of neuropathic pain - 2020-06-25 - 2026-06-26
Neuropathic pain is a chronic pain condition, which can develop when the nerves of the somatosensory nervous system become injured in consequence of various diseases, including tumours, diabetes, multiple sclerosis, HIV infections, or after surgeries. It is estimated that this type of chronic pain affects 6.9-10% of the general population and its pathology is more frequent in women (8%) compared to men (5.7%). Epidemiological studies demonstrate a higher occurrence of pain-related disorders (including migraine, fibromyalgia, arthritis) in women, which is connected with a frequent use of analgesics. Moreover, neuropathic pain is relatively less responsive to opioids than other types of pain, which is possibly due to a disrupted opioid system partially caused by a profound glial cells activation and neuroinflammation. Chronicity of symptoms and not fully understood development mechanisms make neuropathic pain a burning problem for the worldwide healthcare and represent a significant, yet unmet medical need. The results of our recent studies suggest that pharmacological modulation of histamine receptors H3 (H3R) and H4 (H4R) is particularly interesting direction for research on novel therapeutic targets for the management of neuropathic pain.
In the frame of our project we are planning a series of studies designed to investigate the mechanism of H3R and H4R antagonists-induced analgesia during neuropathic pain. The project proposes an innovative and comprehensive series of experiments, including the use of novel H3R and H4R antagonists. Moreover,
keeping in mind that increasing the efficacy of drugs is an important strategy for improving the management of chronic pain, the research tasks proposed in this project focus on the problem of the loss of opioids effectiveness in neuropathy. Our preliminary data show that H3R and H4R antagonists potentiate morphine
analgesia. This important implication of opioid effectiveness raises great hopes for future pain therapy. Therefore, in the present project we are planning to combine clinically used drugs (such as buprenorphine, oxycodone) with H3R and H4R antagonists to improve opioids effectiveness and minimalize therapeutic doses. An important aspect of neuropathic pain is gender-related pain prevalence, which still remains an
unexplored issue. Therefore
