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.

Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents

“…Injection volumes designed to faithfully induce hippocampal SD were about 50 times less than that used to faithfully trigger neocortical SD (i.e., 10 nl vs 0.5 μl) Ingvardsen et al, 1998a). This finding suggests the heightened susceptibility of hippocampus for SD compared with the neocortex (Bureš et al, 1974) with an efficiency for SD induction of 83% vs 58%, respectively, in the present experiments.…”

“…were the first to develop an animal model showing that neocortical SD (in rodents) was sufficient to activate caudal TNC consistent with what might be expected from migraine pain in humans (Moskowitz and Macfarlane, 1993). Later, Ingvardsen et al (1998a) were unable to duplicate this result. Unfortunately, numerous methodological differences between these two studies (Moskowitz and Kraig, 1998) precludes meaningful comparison of their results.…”

Cortical spreading depression and gene regulation: Relevance to migraine

“…31 Furthermore, it must explain the failure of some studies to link CSD with dural extravasation or calcitonin generelated peptide (CGRP) release proposed by the neu- rogenically mediated dural inflammation theory of migraine headache. [32][33][34] It is possible that peptides such as CGRP and substance P, when activated by CSD, diffuse into the subarachnoid space and onto dural afferents. A novel alternative introduced by our results is that some of the painful sensation of migraine may originate in pial afferents.…”

Fisiopatologia da enxaqueca

“…Estas experiências estabeleceram a ligação entre a DA e a ativação do sistema trigeminovascular. Em outro estudo, porém, a expressão de c-fos no núcleo caudal do trigêmeo por DA induzida por injeções de KCl (1M, 5 µL) no hemisfério direito de ratos não se correlacionou com a DA, e sim com as injeções 42 . Noutro estudo interessante, a dilatação dos vasos arteriais na pia-máter de gatos foi medida após a indução de DA 43 , estabelecendo-se a ligação entre a DA e a HA.…”