Santosh Mishra, assistant professor of neuroscience at NC State, was part of a team of NIH researchers who have discovered four previously unknown mediators for itch and pain in the skin. Identifying these mediators may be a first step toward providing relief for people who suffer from chronic skin conditions such as psoriasis. The researchers’ findings appear in Science Signaling. Dr. Mishra agreed to do a Q&A on the research with the Abstract.
The Abstract (TA): What are these mediators and how do they contribute to chronic itch and pain in conditions like psoriasis?
Mishra: The mediators are metabolites; specifically, they are fatty acids. These metabolites are produced by the body in the skin from linoleic acid, which is a type of fat found in food and required (in small amounts) by the human body.
These metabolites were found in much higher amounts in skin samples taken from psoriasis patients. Since other itch and pain inducing compounds are made in higher quantities by the body during disease, overproduction of these metabolites seemed to indicate a connection between the metabolites and the itching and pain. In this study, we found evidence that fatty acid metabolites of linoleic acid can directly activate sensory neurons.
TA: You looked at mediators for itch in skin. What did you find?
Mishra: We collaborated with the lead researcher, Dr. Ramsden from the NIH, to screen eight linoleic acid metabolites for their effects on itch. Out of eight mediators that we screened using a mouse model, we found one – 9K-12,13E-LA – directly connected to itch. We were also able to determine that 9K-12 might be acting through sensory neurons, rather than as part of an immune (allergic) response.
TA: Why would someone with psoriasis have more of these mediators in the skin – would diet or environmental factors cause more of them to develop, leading to chronic itch/pain or does the presence of the chronic condition lead to their overproduction?
Mishra: Higher concentrations of these mediators in the skin could be due to several factors. One factor could be disease (psoriasis) interfering with the metabolic pathway that produces these mediators, leading to overproduction. A diet containing too much linoleic acid could lead to an increase in linoleic acid metabolites which would, in turn, produce higher amounts of these metabolites resulting in an increase of sensory neurons activation. Early results show that reducing the amount of linoleic acid in the diet results in a decrease in these metabolites. This is an area that requires further study.
TA: What are your next steps?
Mishra: This is the beginning of our research and collaboration and we still have many big questions that we need to answer. For instance, what are the receptors through which the lipids work? Are these lipid mediators using histamine-dependent or histamine-independent mechanisms? Which neurotransmitters/neuropeptides do they use to communicate with the neurons in the spinal cord? To answer the role of lipid mediators in itch and pain detection and transmission, we will continue to use bioinformatics, mouse genetics, mouse behavior, cell physiology and pharmacological approaches.
Discovering how these metabolites bind to their receptors and generate signal propagation for itch will be very exciting. Identifying these receptors will allow for the development of drugs that can prevent these mediators from binding to their receptors and possibly alleviate sensations of itch and pain.