A new strategy for the management of inflammatory pain

Summary: M2 macrophages can produce various endogenous opioids, such as endorphins, enkephalin, and dynorphin, which activate opioid receptors at the site of inflammation.

Source: Charite

A group of researchers from Charité – Universitätsmedizin Berlin has discovered a new mechanism of long-lasting pain relief. The cell-signaling protein interleukin-4 induces a specific type of blood cell to produce endogenous opioids at the site of inflammation. The researchers’ findings have been published in the JCI Insight.

Peripheral nerve inflammation can lead to chronic pain. The inflammatory response is mediated by a number of blood-derived immune cells. These produce cytokines, cell-signaling proteins which either enhance or reduce inflammation and pain. Thanks to its anti-inflammatory properties, one of these cytokines – known as interleukin-4 (IL-4) – is already being used to treat pain.

The team, led by Prof. Halina Machelska from Charité’s Department of Experimental Anesthesiology on Campus Benjamin Franklin, used an animal model of sciatic pain to study the analgesic mechanisms of IL-4. Initially, a single injection of IL-4 near the inflamed nerve produced pain relief which only lasted for several minutes. When repeated daily, however, injections reduced pain for up to eight days, even in the absence of further IL-4 injections. This resulted from the IL-4-induced accumulation of M2 macrophages, a type of immune system scavenger cell which produces opioids and thereby reduces pain.

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Isolated M2 macrophages (blue nuclei and red dots) produce endogenous opioids such as enkephalin (green dots). The image is credited to Machelska/ Charité.

Prof. Machelska proposes that not general inhibition of inflammation, but fostering the beneficial properties of the M2 macrophages is most promising to tackle pathological pain. “Our findings are relevant to many immune-mediated diseases, ranging from arthritis to neurodegenerative diseases and cancer.”

The M2 macrophages were then isolated from the inflamed nerve and transferred into a different animal, where they also reduced pain. When the researchers studied the isolated cells in greater detail, they found that these cells produced various endogenous opioids, such as endorphin, enkephalin and dynorphin which activated opioid receptors at the site of inflammation. “As these analgesic effects occur at the peripheral nerves, outside the brain, it is possible to prevent undesirable side effects such as sedation, nausea and addiction,” explains Prof. Machelska. She adds: “These findings may offer new perspectives in our endeavors to develop alternative pain management options for patients.”

About this neuroscience research article

Media Contacts:
Halina Machelska – Charite
Image Source:
The image is credited to Machelska/ Charité.

Original Research: Open access
“IL-4 induces M2 macrophages to produce sustained analgesia via opioids”. Celik MÖ et al.
JCI Insight doi:10.1172/jci.insight.133093133093.


IL-4 induces M2 macrophages to produce sustained analgesia via opioids

IL-4 is a pleiotropic antiinflammatory cytokine, which can be neuroprotective after nervous system injury. The beneficial actions of IL-4 are thought to result from the blunting of action of inflammatory mediators, such as proinflammatory cytokines. Here, we demonstrate that IL-4 induces M2 macrophages to continuously produce opioid peptides and ameliorate pain. IL-4 application at injured nerves in mice shifted F4/80+ macrophages from the proinflammatory M1 to the antiinflammatory M2 phenotype, which synthesized opioid peptides (Met-enkephalin, β-endorphin, and dynorphin A 1-17). These effects were accompanied by a long-lasting attenuation of neuropathy-induced mechanical hypersensitivity, beyond the IL-4 treatment. This IL-4-induced analgesia was decreased by opioid peptide antibodies and opioid receptor (δ, μ, κ) antagonists applied at injured nerves, which confirms the involvement of the local opioid system. The participation of M2 macrophages was supported by analgesia in recipient mice injected at injured nerves with F4/80+ macrophages from IL-4–treated donors. Together, IL-4–induced M2 macrophages at injured nerves produced opioid peptides, which activated peripheral opioid receptors to diminish pain. Fostering the opioid-mediated actions of intrinsic M2 macrophages may be a strategy to tackle pathological pain.

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