title: Possible mechanism of c-fos expression in trigeminal nucleus caudalis following cortical spreading depression.
abstract: Cortical spreading depression (CSD) is characterized by a transient, reversible depression of EEG activity which advances across the cortical surface at a velocity of 2-5 mm/min. CSD was originally linked to the aura phase of migraine, but recently also to migraine headache. The theory is that CSD activates meningeal trigeminal C-fibers causing neurogenic inflammation and pain (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177). The present study is an examination of the proposed link between CSD elicited in rats and activation of trigeminal nerve fibers. Multiple CSDs were elicited unilaterally for 1 h by KCl injections (1 M, 5 microliters) into the right hemisphere, while NaCl (1 M, 5 microliters) was injected into the left as control. After an additional 1 h the animals were sacrificed and trigeminal activation assessed by the expression of c-fos in trigeminal nucleus caudalis (TNC) using immunohistochemistry. The correlation between the number of CSDs and the extent of c-fos expression was determined. In addition the effect of sumatriptan (0.3 mg/kg) and morphine (3 mg/kg) given i.v. 30 min before elicitation of CSD was evaluated. CSD caused increased c-fos expression in lamina I and II of TNC where C-fibers, end, the response being greater ipsilaterally. Morphine, but not sumatriptan, reduced c-fos expression in both the ipsilateral and contralateral TNC by 71% (P < 0.05 and P = 0.19, respectively), confirming that nociceptors have been activated. No positive correlation was seen between the number of CSDs and the extent of c-fos expression in TNC. Instead we observed a positive, linear correlation between the number of KCl injections and the extent of c-fos expression in TNC (correlation coefficient r = 0.709, P < 0.05). We suggest that the C-fiber activation observed is caused by hyperosmolar KCl/NaCl and not CSD. Hence, our results do not support the hypothesis of Moskowitz et al. (Moskowitz, M.A., Nozaki, K. and Kraig, R.P., Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms, J. Neurosci., 13 (1993) 1167-1177) which links CSD with migraine headache.
authors.affiliation: Department of General Pharmacology, Novo Nordisk A/S, Maaloev, Denmark. bkin@novo.dk
authors.forename: B K
authors.initials: BK
authors.lastname: Ingvardsen
authors.forename: H
authors.initials: H
authors.lastname: Laursen
authors.forename: U B
authors.initials: UB
authors.lastname: Olsen
authors.forename: A J
authors.initials: AJ
authors.lastname: Hansen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D013181:Cortical Spreading Depression / Q000502:physiology*; D007150:Immunohistochemistry; D007267:Injections; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018170:Sumatriptan / Q000494:pharmacology; D014018:Tissue Distribution; D014275:Trigeminal Caudal Nucleus / Q000378:metabolism*
chemical_list: D009294:Narcotics; D016760:Proto-Oncogene Proteins c-fos; D011189:Potassium Chloride; D009020:Morphine; D018170:Sumatriptan