Healing Pain

Activation of pain receptors accelerated wound healing

Alice Bakhareva, N+1

Scientists stopped the formation of scars and started the regeneration of damaged mouse tissues using imiquimod, a substance that triggers inflammation. It turned out that imiquimod acts through pain TRPA receptors and innate immunity cells. The authors of an article published in the journal Science Immunology (Wei et al., Activation of TRPA1 nociceptor promotes systemic adult mammalian skin regeneration) suggest that TRPA receptor agonists will help heal wounds in humans as well.

Wound healing can occur in two ways: the damage is either closed by scar connective tissue and a scar is formed, or a full-fledged tissue regeneration occurs. In the second case, all types of tissue cells and its structural organization are restored, and hair follicles and glands appear on the healed area.

Scientists are looking for ways to direct tissue healing along the path of full regeneration and reduce the formation of scars, and the inflammatory process is considered one of the important activators of regeneration. Therefore, a group of scientists from the United States led by Thomas Leung from the Medical School at the University of Pennsylvania suggested that wound healing can accelerate imiquimod – a substance that triggers inflammation (it is used to treat skin cancer or warts). Cream with imiquimod was applied to the ears of mice, in which holes were made with a diameter of two millimeters.

Wounds of animals whose ears were smeared with imiquimod were completely healed within a month after the injury, whereas in control animals (they were given a regular cream), the wound diameter decreased only twice. Imiquimod stimulated the formation of full-fledged skin at the site of the hole (with hair follicles, sweat glands and subcutaneous fat) and even the formation of cartilage, and the control group had a scar at the site of the wound. Interestingly, the damage was delayed faster, even if the second, whole mouse ear was smeared, and the effect was most noticeable if the cream was applied five days before the hole was made.

Wound healing with and without imiquimod (bottom). Figures from the article by Wei et al.

Imiquimod acts on various receptors, and in order to understand which pathway promotes regeneration, scientists damaged and treated the ears of mice knocked out by genes of different receptors. Imiquimod accelerated wound healing in all mice, except those who did not have TRPA1 receptors – ion channels that mediate pain sensitivity. In mice without TRPA1, the holes were less likely to overgrow completely, and instead of a full-fledged tissue, a scar appeared at the wound site.

Wound healing with imiquimod in mice with and without TRPA receptors.

The researchers found out that TRPA1 receptors trigger inflammation through the following chain of signals: they stimulate dendritic skin cells, they secrete interleukin 23, and that activates T-cells of type γδ, which secrete interleukins 17 and 22 and trigger an inflammatory response. Switching off any of these stages disrupted tissue regeneration, and after administration of interleukin 23, imiquimod accelerated wound healing even in mice without TRPA1.

The pathway of imiquimod regeneration activation via TRPA receptors.

Scientists suggest using imiquimod cream or other TRPA1 receptor agonists to heal people's wounds. However, before introducing such an approach into medical practice, it is necessary to conduct a standard series of clinical trials.

It is not the first time that new ways of using Imiquimod have been found: in addition to treating warts and skin cancer, the substance has been proposed to be used to enhance the immune response to the vaccine in the elderly. And with the help of imiquimod, scientists slowed down the movement of mouse spermatozoa with an X chromosome and obtained offspring in which there were almost no females.

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