title: Depressing interleukin-1β contributed to the synergistic effects of tramadol and minocycline on spinal nerve ligation-induced neuropathic pain.
abstract: Our previous study indicated that coadministration of tramadol and minocycline exerted synergistic effects on spinal nerve ligation (SNL)-induced neuropathic mechanical allodynia. However, the underlying mechanisms are still unclear. Recent reports indicated that spinal proinflammatory factor interleukin-1β (IL-1β) contributed to the development of neuropathic pain and the positive feedback communication between neuron and glia. Therefore, the present research is to confirm whether spinal IL-1β-related pathway response contributes to the synergistic effects of tramadol and minocycline on SNL-induced neuropathic pain. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn 3 days after lesion, which could be significantly decreased by tramadol and minocycline coadministration. Immunofluorescence and Western blot indicated that SNL-induced microglial phosphorylated p38 (p-p38) upregulation was also inhibited by tramadol and minocycline coapplication. Meanwhile, intrathecal administration of p38 inhibitor SB203580 markedly alleviated mechanical allodynia whilst reducing IL-1β and Fos expression induced by SNL. Moreover, intrathecal neutralized antibody of IL-1β could depress SNL-induced mechanical allodynia and Fos expression. These results suggest that depressing SNL-induced aberrant activation of the spinal dorsal horn IL-1β-related pathway contributes to the underlying mechanism of the synergistic effects of tramadol and minocycline coadministration on SNL-induced neuropathic mechanical allodynia.
authors.affiliation: Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, PR China.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Mei
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Cheng
authors.initials: C
authors.lastname: Xie
authors.forename: Dan
authors.initials: D
authors.lastname: Wu
authors.forename: Ichinyo
authors.initials: I
authors.lastname: Ho
authors.forename: Junichiro
authors.initials: J
authors.lastname: Kotani
authors.forename: Li-Xian
authors.initials: LX
authors.lastname: Xu
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004338:Drug Combinations; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism*; D008026:Ligation; D008297:Male; D017628:Microglia / Q000378:metabolism; D008911:Minocycline / Q000008:administration & dosage*; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism*; D010766:Phosphorylation; D020671:Posterior Horn Cells / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects; D013127:Spinal Nerves / Q000187:drug effects / Q000378:metabolism* / Q000601:surgery; D014147:Tramadol / Q000008:administration & dosage*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000700:Analgesics; D000906:Antibodies; D004338:Drug Combinations; D007093:Imidazoles; D053583:Interleukin-1beta; D011725:Pyridines; D014147:Tramadol; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline; C093642:SB 203580