title: Gabapentin Effects on PKC-ERK1/2 Signaling in the Spinal Cord of Rats with Formalin-Induced Visceral Inflammatory Pain.
abstract: Currently, the clinical management of visceral pain remains unsatisfactory for many patients suffering from this disease. While preliminary animal studies have suggested the effectiveness of gabapentin in successfully treating visceral pain, the mechanism underlying its analgesic effect remains unclear. Evidence from other studies has demonstrated the involvement of protein kinase C (PKC) and extracellular signal-regulated kinase1/2 (ERK1/2) in the pathogenesis of visceral inflammatory pain. In this study, we tested the hypothesis that gabapentin produces analgesia for visceral inflammatory pain through its inhibitory effect on the PKC-ERK1/2 signaling pathway. Intracolonic injections of formalin were performed in rats to produce colitis pain. Our results showed that visceral pain behaviors in these rats decreased after intraperitoneal injection of gabapentin. These behaviors were also reduced by intrathecal injections of the PKC inhibitor, H-7, and the ERK1/2 inhibitor, PD98059. Neuronal firing of wide dynamic range neurons in L6-S1 of the rat spinal cord dorsal horn were significantly increased after intracolonic injection of formalin. This increased firing rate was inhibited by intraperitoneal injection of gabapentin and both the individual and combined intrathecal application of H-7 and PD98059. Western blot analysis also revealed that PKC membrane translocation and ERK1/2 phosphorylation increased significantly following formalin injection, confirming the recruitment of PKC and ERK1/2 during visceral inflammatory pain. These effects were also significantly reduced by intraperitoneal injection of gabapentin. Therefore, we concluded that the analgesic effect of gabapentin on visceral inflammatory pain is mediated through suppression of PKC and ERK1/2 signaling pathways. Furthermore, we found that the PKC inhibitor, H-7, significantly diminished ERK1/2 phosphorylation levels, implicating the involvement of PKC and ERK1/2 in the same signaling pathway. Thus, our results suggest a novel mechanism of gabapentin-mediated analgesia for visceral inflammatory pain through a PKC-ERK1/2 signaling pathway that may be a future therapeutic target for the treatment of visceral inflammatory pain.
authors.affiliation: Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, China.
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Affiliated Hospital of Taishan Medical University, Taian, China.
authors.forename: Zheng-Dong
authors.initials: ZD
authors.lastname: Guo
authors.affiliation: Department of Neurology, Shandong Taishan Chronic Disease Hospital, Taian, China.
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Li
authors.affiliation: Department of Neurology, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Fong
authors.affiliation: Department of Pharmacology, College of Pharmacy, Taishan Medical University, Taian, China.
authors.forename: Ji-Guo
authors.initials: JG
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, China.
authors.forename: Can-Wen
authors.initials: CW
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, United States of America.
authors.forename: Ke-Rui
authors.initials: KR
authors.lastname: Gong
authors.affiliation: Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Yang
authors.affiliation: Department of Neurology, Affiliated Hospital of Taishan Medical University, Taian, China.
authors.forename: Jing-Zhong
authors.initials: JZ
authors.lastname: Niu
authors.affiliation: Hypoxia Medical Institute, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Xun-Ming
authors.initials: XM
authors.lastname: Ji
authors.affiliation: Hypoxia Medical Institute, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: Lv
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal; D002462:Cell Membrane / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena; D005419:Flavonoids / Q000494:pharmacology; D005557:Formaldehyde / Q000009:adverse effects; D000077206:Gabapentin; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D059408:Pain Management; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*; D059265:Visceral Pain / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D005419:Flavonoids; D005557:Formaldehyde; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one