Opioids in pain control by M2 macrophages and M2 microglia
Final Report Abstract
IL-4 is an anti-inflammatory cytokine, which can be protective in inflammatory and neurologic disorders, and can alleviate pain. The beneficial actions of IL-4 are thought to result from decreasing the activity of inflammatory mediators, such as proinflammatory cytokines. In this project we demonstrated that, (a) IL-4 injection can reduce pain responses in an animal model via release of opioid peptides from immune cells (M1 macrophages) at injured nerves and (b) repeated IL-4 treatment induces M2 macrophages to continuously produce opioid peptides and ameliorate pain. As a model of neuropathic pain, we used chronic constriction injury (CCI) of the sciatic nerve in male mice. Injured nerves were predominately infiltrated by proinflammatory M1 macrophages and IL-4 did not change their numbers or phenotype. These macrophages secreted opioid peptides after mobilization of calcium from intracellular stores. When IL-4 was applied repeatedly, antiinflammatory M2 macrophages synthesized opioid peptides continuously. These effects were accompanied by a long-lasting attenuation of neuropathy-induced mechanical pain responses. Fostering such opioid-mediated actions of macrophages may be a strategy to tackle pathological pain without eliciting adverse central side effects such as apnea or addiction.
Publications
- IL-4 induces M2 macrophages to produce sustained analgesia via opioids. JCI Insight 2020, 27;5(4):e133093
Celik MÖ, Labuz D, Keye J, Glauben R, Machelska H
(See online at https://doi.org/10.1172/jci.insight.133093) - Immune cell-mediated opioid analgesia. Immunol Lett 2020, 227:48-59
Celik MÖ, Machelska H
(See online at https://doi.org/10.1016/j.imlet.2020.08.005) - Opioid Receptors in Immune and Glial Cells-Implications for Pain Control. Front Immunol 2020, 4;11:300
Celik MÖ, Machelska H
(See online at https://doi.org/10.3389/fimmu.2020.00300) - Interleukin-4 Induces the Release of Opioid Peptides from M1 Macrophages in Pathological Pain. J Neurosci 2021, 31;41(13):2870-2882
Labuz D, Celik MÖ, Seitz V, Machelska H
(See online at https://doi.org/10.1523/jneurosci.3040-20.2021) - Real-Time Quantitative Reverse Transcription PCR for Detection of Opioid Receptors in Immune Cells. Opioid Receptors 2021, 83-95
Celik MÖ, Labuz D, Machelska H
(See online at https://doi.org/10.1007/978-1-0716-0884-5_8)
