Sustained Elevated Adenosine via ADORA2B Promotes Chronic Pain through Neuro-immune Interaction.
The molecular mechanisms of chronic pain are poorly understood and effective mechanism-based treatments are lacking. Here, we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected chronic mechanical and thermal hypersensitivity due to sustained elevated circulating adenosine. Extending from Ada(-/-) mice, we further discovered that prolonged elevated adenosine contributed to chronic pain behaviors in two additional independent animal models: sickle cell disease mice, a model of severe pain with limited treatment, and complete Freund's adjuvant paw-injected mice, a well-accepted inflammatory model of chronic pain. Mechanistically, we revealed that activation of adenosine A2B receptors on myeloid cells caused nociceptor hyperexcitability and promoted chronic pain via soluble IL-6 receptor trans-signaling, and our findings determined that prolonged accumulated circulating adenosine contributes to chronic pain by promoting immune-neuronal interaction and revealed multiple therapeutic targets.
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Anesthesiology, Third XiangYa Hospital, Central South University, Hunan 440851, China.
Xia
X
Hu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
Morayo G
MG
Adebiyi
Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Jialie
J
Luo
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
Kaiqi
K
Sun
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Thanh-Thuy T
TT
Le
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Yujin
Y
Zhang
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Hongyu
H
Wu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Shushan
S
Zhao
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Harry
H
Karmouty-Quintana
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
Hong
H
Liu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Aji
A
Huang
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Yuan Edward
YE
Wen
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Oleg L
OL
Zaika
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Mykola
M
Mamenko
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Oleh M
OM
Pochynyuk
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
Rodney E
RE
Kellems
Department of Anesthesiology, The University of Colorado, Aurora, CO 80045, USA.
Holger K
HK
Eltzschig
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA.
Michael R
MR
Blackburn
Integrative Biology and Pharmacology, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Edgar T
ET
Walters
Department of Anesthesiology, Third XiangYa Hospital, Central South University, Hunan 440851, China.
Dong
D
Huang
Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Hongzhen
H
Hu
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, Houston, TX 77030, USA. Electronic address: yang.xia@uth.tmc.edu.
Yang
Y
Xia
D000241:Adenosine / Q000097:blood / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000378:metabolism; D000755:Anemia, Sickle Cell / Q000150:complications / Q000473:pathology; D000818:Animals; D001522:Behavior, Animal; D059350:Chronic Pain / Q000097:blood / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D009420:Nervous System / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D009619:Nociceptors / Q000378:metabolism; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012018:Reflex; D050796:STAT3 Transcription Factor / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000473:pathology; D015398:Signal Transduction; D012995:Solubility; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D015850:Interleukin-6; D043704:Receptor, Adenosine A2B; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000243:Adenosine Deaminase; D000241:Adenosine