Do gabapentin or pregabalin directly modulate the µ receptor?

Area of Science:

• Pharmacology
• Neuroscience
• Molecular Biology

Background:

• Pregabalin and gabapentin are used for neuropathic pain but concerns exist about misuse, especially with opioids.
• Co-ingestion of gabapentinoids with opioids is linked to increased opioid-related deaths.
• The molecular mechanisms underlying these enhanced risks are not fully understood.

Purpose of the Study:

• To investigate if pregabalin or gabapentin directly modulate mu-opioid receptor signaling.
• To determine if these drugs affect morphine's activation of the mu-opioid receptor.

Main Methods:

• HEK 293 cells expressing human mu-receptors were used to assess pregabalin/gabapentin effects on morphine-induced responses.
• Assays included membrane potential, cAMP production, and ERK phosphorylation.
• Effects on morphine-induced hyperpolarization were also studied in AtT20 cells.

Main Results:

• Pregabalin and gabapentin did not activate the mu-opioid receptor or alter morphine's effects on K+ channel activation or ERK phosphorylation.
• Neither drug affected morphine-induced receptor desensitization.
• High-concentration pregabalin (100 µM) increased cAMP production independently of morphine.

Conclusions:

• Data do not support direct or allosteric modulation of the mu-opioid receptor by pregabalin or gabapentin.
• The findings do not explain how these drugs might augment opioid effects.
• Further research is needed to understand the mechanisms behind increased opioid-related harms with co-ingestion.