title: Inhibition of p38 mitogen-activated protein kinase activation in the rostral anterior cingulate cortex attenuates pain-related negative emotion in rats.
abstract: The emotional components of pain are far less studied than the sensory components. Previous studies have indicated that the rostral anterior cingulate cortex (rACC) is implicated in the affective response to noxious stimuli. Activation of p38 mitogen-activated protein kinase (MAPK) in the spinal cord has been documented to play an important role in diverse kinds of pathological pain states. We used formalin-induced conditioned place aversion (F-CPA) in rats, an animal model believed to reflect the emotional response to pain, to investigate the involvement of p38 MAPK in the rACC after the induction of affective pain. Intraplantar formalin injection produced a significant activation of p38 MAPK, as well as mitogen-activated kinase kinase (MKK) 3 and MKK6, its upstream activators, in the bilateral rACC. p38 MAPK was elevated in both NeuN-positive neurons and Iba1-positive microglia in the rACC, but not GFAP-positive cells. Blocking p38 MAPK activation in the bilateral rACC using its specific inhibitor SB203580 or SB239063 dose-dependently suppressed the formation of F-CPA. Inhibiting p38 MAPK activation did not affect formalin-induced two-phase spontaneous nociceptive response and low intensity electric foot-shock induced CPA. The present study demonstrated that p38 MAPK signaling pathway in the rACC contributes to pain-related negative emotion. Thus, a new pharmacological strategy targeted at the p38 MAPK cascade may be useful in treating pain-related emotional disorders.
authors.affiliation: Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: hongcao@fudan.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Cao
authors.affiliation: Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Kai-Kai
authors.initials: KK
authors.lastname: Zang
authors.affiliation: Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.affiliation: Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Zhi-Qi
authors.initials: ZQ
authors.lastname: Zhao
authors.affiliation: Department of Integrative Medicine and Neurobiology, Institutes of Brain Research, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Gen-Cheng
authors.initials: GC
authors.lastname: Wu
authors.affiliation: Institute of Neurobiology, Institute of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Yu-Qiu
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology*; D004644:Emotions / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005557:Formaldehyde; D006179:Gyrus Cinguli / Q000201:enzymology*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000201:enzymology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048053:Mitogen-Activated Protein Kinase 6 / Q000378:metabolism; D009474:Neurons / Q000201:enzymology; D059225:Nociception / Q000502:physiology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D005557:Formaldehyde; D048052:Mitogen-Activated Protein Kinase 3; D048053:Mitogen-Activated Protein Kinase 6; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: Anterior cingulate cortex; Formalin-induced conditioned place aversion; Pain-related negative emotion; p38 MAPK