Activation of NPFFR2 leads to hyperalgesia through the spinal inflammatory mediator CGRP in mice.
Neuropeptide FF (NPFF) is recognized as an opioid modulating peptide that regulates morphine-induced analgesia. The aim of this study was to delineate the role of NPFFR2 in pain transmission. We found the expression levels of NPFF and NPFFR2 were increased in the lumbar dorsal horn of animals with CFA- and carrageenan-induced inflammation and both NPFFR2 over-expressing transgenic (NPFFR2-Tg) and NPFFR2 agonist-treated mice displayed hyperalgesia. BOLD signals from functional MRI showed that NPFFR2-Tg mice exhibited increased activation of pain-related brain regions after painful stimulation when compared to WT mice. Inflammatory mediators within the spinal cord, calcitonin gene-related peptide (CGRP) and substance P (SP), were up-regulated in NPFFR2-Tg and chronic NPFFR2 agonist-treated mice. In DRG cultures, treatment with an NPFFR2 agonist induced the expression and release of CGRP, an action which was blocked by NPFFR2 siRNA. Furthermore, treatment with a CGRP antagonist ameliorated the pain hyperalgesia in NPFFR2-Tg mice, returning the pain threshold to a control level. However, treatment with a SP antagonist reduced the pain responses in both WT and NPFFR2-Tg mice and did not suppress pain hypersensitivity in NPFFR2-Tg mice. Together, these results demonstrate that NPFFR2 activation modulates pain transmission by up-regulating the pain mediator CGRP, leading to hyperalgesia.
Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wen-Hwa 1st Rd., Taoyuan, 333, Guishan, Taiwan. Electronic address: yatin@mail.cgu.edu.tw.
Ya-Tin
YT
Lin
Department of Imaging Physics, The University of Texas MD Anderson Cancer Center, No. 1400 Pressler St., TX 77030-4009, Houston, USA. Electronic address: HLALiu@mdanderson.org.
Ho-Ling
HL
Liu
Department of Anesthesiology, Hualein Tzu Chi Hospital & Tzu Chi University, Tzu Chi Foundation, No. 707, Chung Yang Rd., 970 Hualien, Taiwan. Electronic address: yd3j@msn.com.
Yuan-Ji
YJ
Day
Department of Chemistry, Fu Jen Catholic University, No. 510, Zhongzheng Road, Xinzhuang Dist. 242, New Taipei City, Taiwan. Electronic address: 080686@mail.fju.edu.tw.
Che-Chien
CC
Chang
Department of Electrical Engineering, Chang Gung University, Taoyuan, Taiwan; Center for Advanced Molecular Imaging and Translation, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Electronic address: phhsu@mail.cgu.edu.tw.
Po-Hung
PH
Hsu
Graduate Institute of Biomedical Sciences, Department of Physiology and Pharmacology, Chang Gung University, No. 259 Wen-Hwa 1st Rd., Taoyuan, 333, Guishan, Taiwan; Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan; Neuroscience Research Center, Chang Gung Memorial Hospital, No. 5, Fusing St., Taoyuan, 333, Guishan, Taiwan. Electronic address: jinchen@mail.cgu.edu.tw.
Jin-Chung
JC
Chen
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D002351:Carrageenan / Q000633:toxicity; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000000981:diagnostic imaging; D004195:Disease Models, Animal; D005552:Forelimb / Q000294:innervation; D005620:Freund's Adjuvant / Q000633:toxicity; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000235:genetics*; D006834:Hydrazines / Q000494:pharmacology; D006930:Hyperalgesia / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009187:Myelitis / Q000139:chemically induced / Q000150:complications*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D010147:Pain Measurement; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
C000599125:AC-263093; D006834:Hydrazines; C470191:MrgA1 protein, mouse; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D002351:Carrageenan; D005620:Freund's Adjuvant; D015740:Calcitonin Gene-Related Peptide; D010100:Oxygen
CGRP; DRG; Hyperalgesia; NPFFR2; Neuropeptide FF (NPFF); Pain transmission