About one million people develop a parasitic disease called cutaneous leishmaniasis each year. The parasite is spread through sand fly bites and causes nasty skin sores, but for many people the wounds are surprisingly painless. For decades, scientists have puzzled over the secret of these painless skin lesions.
"No one knows why these lesions are painless, but it has been thought that the parasite somehow manipulates the host's physiological systems," said Abhay Satoskar, senior author of a new study exploring this unusual phenomenon.
Most research so far has focused on how the parasite appears to increase production of inflammatory molecules called cytokines. Pain neurons (also called nociceptive neurons) express a large number of cytokine receptors. This is one way the immune system increases or decreases the perception of pain.
It is thought that the leishmaniasis parasite can shut down pain signals by hijacking the activity of cytokines. But this hypothesis has never fully explained this unusual phenomenon. For example, some cytokines can enhance pain signals. So Satorska and colleagues set out to examine more broadly what types of metabolic changes these parasitic lesions trigger.
"Even if analgesia is observed, changes in cytokine expression do not appear to be responsible for this phenotype alone," the researchers wrote in the newly published study. "These observations led us to hypothesize that other non-immune mediators produced or upregulated during Leishmania infection may directly mediate antinociception at the lesion site."
The study investigated various metabolites produced at the lesion site after mice were infected with Leishmania. Research has identified three specific anti-nociceptive mediators: endogenous purines, arachidonic acid, and endocannabinoid metabolites.
These metabolic pathways are all linked in some way to pain signaling, suggesting that this cunning parasite's analgesic technique cannot be entirely attributed to the activity of cytokines.
"The infection creates some effects in the cells that may be direct or indirect -- we don't know," Satoska said. "But the environment created by the infection results in the production of these metabolites. What's exciting is that this is the first time we're starting to understand why there's no cellular basis for pain in these lesions."
Of course, these findings also raise a host of new questions for researchers to explore. If these are metabolic pathways that inhibit lesion pain, how exactly do parasites activate these pathways?
Curiously, previous research has shown that when patients with cutaneous leishmaniasis develop a secondary bacterial infection, they tend to report increased wound pain. Therefore, in the case of secondary infection, the process of blocking pain pathways is often overridden.
Satorska believes that if future research can find out exactly how these pain signaling pathways are blocked, an entirely new class of analgesic drugs could be developed - drugs that block pain directly at the wound site, rather than the current opioids that work in different parts of the brain: "Based on our data, something the parasites do triggers pathways that inhibit pain. How they do this is something we're still studying. We hypothesize that any molecules produced by the parasite's presence could be potential painkillers for other health problems."
The new research is published in the journal iScience.