title: Signaling Mechanism of Cannabinoid Receptor-2 Activation-Induced β-Endorphin Release.
abstract: Activation of cannabinoid receptor-2 (CB2) results in β-endorphin release from keratinocytes, which then acts on primary afferent neurons to inhibit nociception. However, the underlying mechanism is still unknown. The CB2 receptor is generally thought to couple to Gi/o to inhibit cAMP production, which cannot explain the peripheral stimulatory effects of CB2 receptor activation. In this study, we found that in a keratinocyte cell line, the Gβγ subunits from Gi/o, but not Gαs, were involved in CB2 receptor activation-induced β-endorphin release. Inhibition of MAPK kinase, but not PLC, abolished CB2 receptor activation-induced β-endorphin release. Also, CB2 receptor activation significantly increased intracellular Ca(2+). Treatment with BAPTA-AM or thapsigargin blocked CB2 receptor activation-induced β-endorphin release. Using a rat model of inflammatory pain, we showed that the MAPK kinase inhibitor PD98059 abolished the peripheral effect of the CB2 receptor agonist on nociception. We thus present a novel mechanism of CB2 receptor activation-induced β-endorphin release through Gi/o-Gβγ-MAPK-Ca(2+) signaling pathway. Our data also suggest that stimulation of MAPK contributes to the peripheral analgesic effect of CB2 receptor agonists.
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Fang
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Ling-Hong
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Tang-Feng
authors.initials: TF
authors.lastname: Su
authors.affiliation: Biomolecular Physics and Modeling Group, Department of Physics, Huazhong University of Science and Technology, Wuhan, 430074, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Biomolecular Physics and Modeling Group, Department of Physics, Huazhong University of Science and Technology, Wuhan, 430074, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Peng
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Cai-Hua
authors.initials: CH
authors.lastname: Wu
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Xiao-Cui
authors.initials: XC
authors.lastname: Yuan
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Sun
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Xian-Fang
authors.initials: XF
authors.lastname: Meng
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Tian
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Pan
authors.affiliation: Department of Neurobiology and Key Laboratory of Neurological Diseases of Ministry of Education, The Institute of Brain Research, School of Basic Medicine, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China. liman7322@hotmail.com.
authors.forename: Man
authors.initials: M
authors.lastname: Li
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism*
chemical_list: C439263:AM 1241; D000700:Analgesics; D002186:Cannabinoids; D043885:Receptor, Cannabinoid, CB2; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D020962:Heterotrimeric GTP-Binding Proteins; D002118:Calcium
keywords: Analgesia; Cannabinoid receptors; G proteins; Gβγ; Keratinocytes; MAPK; β-Endorphin