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Tesi Macchiarulo - Pathos

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Tesi Macchiarulo


Master's thesis

Pathos 2026; 33.2. Online 2026, Jun 02
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Postgraduate student: Rosanna Macchiarulo
Supervisor: Paolo Marchettini

School of Human Health Sciences
             Level II Master’s Degree
in Advanced Training and Qualification
in Pain Management
University of Florence
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Summary

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Riassunto

La review an.................................

Key words

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Parole chiave

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Introduction

Throughout history, the management of pain has been a primary concern for humanity. This has been addressed through diverse methodologies, encompassing physical techniques, surgical procedures, empirical practices, and, with increasing prominence, the utilisation of pharmacological substances. Among these, natural analgesics have played a central role, particularly opium extracts.
The use of opium, derived from the plant Papaver somniferum, has its origins in antiquity. As early as 5,000 years ago, the Sumerian civilisations documented the use of preparations obtained from the plant, known as Hu gil, or 'plant of joy', highlighting its analgesic and sedative effects (Jones, 2019). Subsequently, in the 3rd century BC, Theophrastus referred to the latex extracted from the poppy as 'opos' (????), from which the word 'opium' derives.
In the Greek and Roman worlds, opium-based preparations were utilised for the management of pain, sedation and the alleviation of conditions such as joint and chest pain (Smith, 2019). In parallel with this, opium was utilised in both Jewish tradition and Arab medicine for the purpose of alleviating pain, inducing sleep during surgical procedures, and reducing suffering. This practice contributed to the dissemination of opium across Europe and the Middle East. As time passed, the practice was also adopted for the treatment of infectious diseases, including dysentery, and was incorporated into the curriculum of medieval European medical schools, such as those in Salerno and Bologna.


Ethical dilemmas

The hypothesis that organoids may occupy a minimal level of sentience suggests, from a consequentialist perspective, an obligation to minimize their suffering. This introduces the need to balance the potential harm inflicted on entities endowed with rudimentary sensitivity against the benefits of biomedical research. However, the use of organoids as mere experimental means raises deontological objections, exacerbated by their total inability to communicate or manifest internal states.
An analogy has been drawn with animal experimentation: as in that case, the issue is whether the benefits justify pain and suffering. Unlike animals, however, organoids lack output channels that would allow the inference of subjective states, making the interpretation of neural correlates of pain problematic.
The 2021 report by the National Academy of Sciences, Engineering and Medicine emphasizes that pain cannot be reduced to mere nociceptive activation and that its circuitry is still incompletely understood. It follows that it is currently impossible to determine which neural configurations are sufficient to generate a painful experience. Two distinct problems therefore remain open: whether organoids actually experience pain and whether they possess the capacities required to perceive it.

Assembloids and the transmission of painful stimuli

The development of multiregional assembloids has increased the functional complexity of these models. In particular, these systems integrate different organoid components representing four brain regions – somatosensory, spinal, thalamic, and cortical – in order to reconstruct the circuitry involved in pain transmission.  Recent studies show coordinated, spontaneous, and synchronous activity in response to nociceptive stimuli, as well as the usefulness of these models for analyzing genetic variants associated with insensitivity or hyperalgesia. Despite this, such assembloids appear to be limited to signal transmission without generating subjective experiences, which would require further levels of brain integration.  However, the prospect of further increasing their complexity renders this distinction potentially unstable and strengthens the urgency of anticipatory ethical criteria.

The case of chimeras

Human-animal chimeras, obtained through the transplantation of human stem cells into animal brains, raise even more pressing ethical questions. In these organisms, the possibility of forms of consciousness appears less remote, making it urgent to define criteria for determining their moral status and the protections they should be afforded. The issue concerns not only physical suffering but also the possible emergence of complex mental states in biologically non-human organisms, with the risk of anomalous existential conditions. In this context of “moral confusion,” existing regulatory frameworks – such as those concerning animal welfare – prove partially inadequate.
The literature reveals a wide heterogeneity of positions, while converging on the need to ensure adequate levels of care and protection, especially for organisms with advanced cognitive capacities.  At the same time, international guidelines are continuously updated, reflecting the rapid pace of scientific progress.

Conclusions

Taken together, organoids, assembloids, and chimeras challenge established ethical categories, requiring a reconsideration of the criteria for attributing moral status under conditions of profound scientific uncertainty. This gives rise to the need for a regulatory framework that is both flexible and rigorous, capable of accompanying technological development without being reduced to a merely ex post reaction.

Conflict of interests

The authors declare that the study and this article were conducted without any conflict of interest.
Open Access licence (CC BY-NC 4.0). Read Non-Commercial license

Published

15th May 2026

Suggested reading

Saway T et al. The Ethics of Cerebral Organoids Research: Being Conscious of Consciousness. Stem Cell Reports 2019; (13): 440-447.
Trujillo CA et al. Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development. Cell Stem Cell 2019; (25): 558-569.e7.
Farahany NA et al. The ethics of experimenting with human brain tissue. Nature 2018; (556): 429-432.
Sharma A et al. Scientific and Ethical Uncertainties in Brain Organoid Research. Am J Bioeth 2021; (21): 48-51.
Lavazza A, Massimini M. Cerebral organoids: ethical issues and consciousness assessment. J Med Ethics 2018; (44): 606-610.
Greely HT. Human Brain Surrogates Research: The Onrushing Ethical Dilemma. Am J Bioeth 2020; (21): 34-45.
The Emerging Field of Human Neural Organoids, Transplants, and Chimeras. National Academies Press, Washington 2021.
Kim J et al. Human assembloid model of the ascending neural sensory pathway. Nature 2025; (642): 143-153.
Goldman B. By Re-creating neural pathway in dish. Stanford Medicine research may speed pain treatment. Anesthesiology & Pain Management April 09 2025.
Hyun I et al. Ethical Standards to Human-to-Animal Chimera Experiments in Stem Cell Research. Cell Stem Cell 2007; (1): 159-163.
Hübner D. Human-Animal Chimeras and Hybrids: An Ethical Paradox behind Moral Confusion? J Med Philos 2018; (43): 187–210.
Brown J. et al. A Technological and Regulatory Review on Human–Animal Chimera Research: The Current Landscape of Biology, Law, and Public Opinion. Cell Transplant 2023; (32): 1-18.
Kwisda K et al. Ethical arguments concerning human-animal chimera research: a systematic review. BMC Med Ethics 2020; (21): 24.

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