Engineering human spinal microphysiological systems to model opioid-induced tolerance

Area of Science:

• Neuroscience
• Biotechnology
• Pharmacology

Background:

• Opioids are vital for chronic pain but can cause tolerance and hyperalgesia, limiting their effectiveness.
• Current models inadequately represent human mechanisms of opioid-induced tolerance and hyperalgesia.
• Understanding these human mechanisms is crucial for developing safer and more effective pain treatments.

Purpose of the Study:

• To engineer novel human spinal microphysiological systems (MPSs) for modeling human nociception and opioid-induced tolerance.
• To integrate plug-and-play neural activity sensing for real-time measurement of neural responses.
• To investigate the neurochemical and functional changes associated with opioid exposure in a human-relevant model.

Main Methods:

• Development of human spinal MPSs using flattened human spinal cord organoids derived from stem cells.
• Integration of a 3D printed holder for plug-and-play neural activity measurement.
• Exposure of MPSs to prolonged opioid treatment to assess tolerance and hyperalgesia markers.

Main Results:

• The flattened organoid design improved neuron maturation, neural activity, and functional development while reducing hypoxia and necrosis.
• Prolonged opioid exposure induced neurochemical changes indicative of tolerance and hyperalgesia, including altered neural activity.
• Downregulation of μ-opioid receptor expression was observed following sustained opioid treatment in the MPSs.

Conclusions:

• Engineered human spinal MPSs provide a scalable, cost-effective, and user-friendly platform for studying human pain.
• These systems accurately model opioid-induced tolerance and hyperalgesia, offering a significant advancement over existing methods.
• The MPSs demonstrate translational potential for pain etiology research, drug screening, and therapeutic validation in pain medicine.