Research reveals that pain-blocking neurotransmitters offer long-term relief in mice

In mice with spinal cord or peripheral nerve injuries, an international team of researchers headed by scientists at the University of California San Diego School of Medicine found that a gene therapy that prevents targeted nerve cell signaling substantially lower neuropathic pain with no detectable side effects.

Research reveals that pain-blocking neurotransmitters offer long-term relief in mice
Senior study author Martin Marsala, MD, is a professor in the Department of Anesthesiology at UC San Diego School of Medicine. Image Credit: UC San Diego Health Sciences.

The results, which were published in the online issue of Molecular Therapy on May 5th, 2022, might lead to a new therapeutic alternative for a disorder that affects more than half of patients with spinal cord injuries. Damage or dysfunction of nerves elsewhere in the body causes numbness, tingling, muscular weakness, and pain, which can be persistent or severe.

There are no one-size-fits-all treatments for neuropathy. Pharmaceutical therapy, for example, may need complex, continuous drug administration and is accompanied by negative side effects including sedation and motor weakness. Opioids are beneficial, but they can also raise tolerance and increase the risk of misuse or addiction.

Because doctors and researchers can specify the exact site of a spinal cord injury and the source of neuropathic pain, there has been a lot of work put into developing treatments that specifically target injured or impaired neurons in the affected spinal segments.

Gene therapy has been an increasingly attractive choice in recent years. Researchers infected mice with sciatic nerve injury and neuropathic pain with a harmless adeno-associated virus encoding a pair of transgenes that encode for gamma-aminobutyric acid, or GABA. GABA is a neurotransmitter that inhibits the transmission of pain signals between nerve cells.

The transgenes—GAD65 and VGAT—were delivered and expressed just in the region of sciatic nerve damage in the mice, resulting in no obvious side effects such as motor weakening or loss of normal sensation. The transgenes’ synthesis of GABA caused detectable suppression of pain-signaling neurons in mice, which lasted for at least 2.5 months after therapy.

One of the prerequisites of a clinically acceptable antinociceptive (pain-blocking) therapy is minimal or no side effects like muscle weakness, general sedation or development of tolerance for the treatment. A single treatment invention that provides long-lasting therapeutic effect is also highly desirable. These finding suggest a path forward on both.”

Martin Marsala, MD, Study Senior Author and Professor, Department of Anesthesiology, University of California San Diego School of Medicine

Source:
Journal reference:

Tadokoro, T., et al. (2022) Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain. Molecular Therapy. doi.org/10.1016/j.ymthe.2022.04.023.

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