title: Docosahexaenoic acid confers analgesic effects after median nerve injury via inhibition of c-Jun N-terminal kinase activation in microglia.
abstract: The c-Jun N-terminal kinase (JNK) in the central nervous system plays a critical role in the processing of neuropathic pain. Docosahexaenoic acid (DHA), a predominant omega-3 polyunsaturated fatty acid in the central nervous system, has a neuroprotective efficacy. In this study, we examined the relationships between JNK activation in the cuneate nucleus (CN) and behavioral hypersensitivity after chronic constriction injury (CCI) of the median nerve. We further investigated the effects of DHA administration on JNK activation and development of hypersensitivity. Using immunohistochemistry and immunoblotting, low levels of phosphorylated JNK (p-JNK) were detected in the CN of sham-operated rats. As early as 1 day after CCI, p-JNK levels in the ipsilateral CN were significantly increased and peaked at 7 days. Double-immunofluorescence labeling with cell-specific markers showed that p-JNK immunoreactive cells coexpressed OX-42, a microglia activation marker, suggesting the expression of p-JNK in the microglia. Microinjection of SP600125, a JNK inhibitor, into the CN 1 day after CCI attenuated injury-induced behavioral hypersensitivity in a dose-dependent manner. Furthermore, animals received intravenous injection of DHA at doses of 100, 250 or 500 nmol/kg 30 min after median nerve CCI. DHA treatment decreased p-JNK and OX-42 levels, diminished the release of proinflammatory cytokines and improved behavioral hypersensitivity following CCI. In conclusion, median nerve injury-induced microglial JNK activation in the CN modulated development of behavioral hypersensitivity. DHA has analgesic effects on neuropathic pain, at least in part, by means of suppressing a microglia-mediated inflammatory response through the inhibition of JNK signaling pathway.
authors.affiliation: Department of Internal Medicine and Traumatology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chun-Ta
authors.initials: CT
authors.lastname: Huang
authors.affiliation: Graduate Institute of Basic Medicine and School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan. Electronic address: med0056@mail.fju.edu.tw.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Tsai
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008475:Median Nerve / Q000293:injuries*; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D000873:Anthracenes; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D004281:Docosahexaenoic Acids; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Docosahexaenoic acid; Median nerve; Microglia; Neuropathic pain; c-Jun N-terminal kinase