Around one million people every year suffer from a parasitic condition known as cutaneous leishmaniasis. Spread by sandfly bites, the parasite causes nasty skin ulcerations but for many people the wounds are unexpectedly pain-free. For decades scientists have been puzzled by the mystery of these painless lesions.
“No one knows why these lesions are painless – but it has been thought that the parasite somehow manipulates the host physiological system,” says Abhay Satoskar, senior author on a new study exploring the unusual phenomenon.
To date, most research has focused on the way this parasite seems to heighten production of inflammatory molecules known as cytokines. Pain neurons (also referred to as nociceptive neurons) express lots of cytokine receptors. This is one way the immune system can turn our sense of pain up or down.
It has generally been thought that the Leishmania parasite can somehow switch off pain signaling by hijacking cytokine activity. But that hypothesis has never fully explained this unusual phenomenon. Some cytokines, for example, can enhance pain signaling. So Satoskar and colleagues set out to more broadly look at what kinds of metabolic changes are triggered by these parasitic lesions.
“Even when analgesia was observed, changes in the expression of cytokines alone did not seem to be responsible for this phenotype,” the researchers write in a newly published study. “These observations led us to hypothesize that other non-immunological mediators produced or upregulated during Leishmania infection may directly mediate anti-nociception at the lesion site.”
The investigations looked at the variety of metabolites produced in lesions when mice were infected with a Leishmania parasite. Three specific anti-nociceptive mediators were identified: endogenous purines, arachidonic acid, and endocannabinoid metabolites.
Each of these metabolic pathways can be linked in some way to pain signaling, suggesting the pain-killing techniques of this crafty parasite cannot be solely attributed to cytokine activity.
“The infection does something in the cell that could be a direct or indirect effect – we don’t know,” Satoskar says. “But the environment that the infection creates leads to production of these metabolites. The exciting thing is that this is the first time we’ve begun to understand the cellular basis of why there is no pain in these lesions.”
Of course, these findings raise a whole host of new questions for the researchers to explore. If these are the metabolic pathways by which pain from the lesions is suppressed then how exactly does the parasite activate these pathways?
Curiously, prior studies have shown that when a patient with cutaneous leishmaniasis experiences a secondary bacterial infection they tend to report pain returning to their wounds. So whatever process is blocking the pain pathway tends to be overridden in the presence of a subsequent infection.
According to Satoskar, if future research can home in on exactly how these pain signaling pathways are blocked then entirely new kinds of analgesic drugs could be developed – medicines that block pain directly at the site of a wound, as opposed to current opioid-based drugs that work in various parts of the brain.
“Based on our data, something the parasites do triggers pathways that suppress pain,” Satoskar adds. “How they do that, we’re still investigating. We hypothesize that any molecules the parasite’s presence is producing could be potential painkillers for other health problems.”
The new study was published in the journal iScience.
Source: Ohio State University