Neocortical spreading depression provokes the expression of c-fos protein-like immunoreactivity within trigeminal nucleus caudalis via trigeminovascular mechanisms

Abstract

The effects of neocortical spreading depression (SD) on the expression of immunoreactive c-fos protein were examined within the superficial laminae of trigeminal nucleus caudalis (TNC), a brainstem region processing nociceptive information. KCl was microinjected into the left parietal cortex at 9 min intervals over 1 hr, and SD was detected by a shift in interstitial DC potential within adjacent frontal cortex. The stained cells in lower brainstem and upper cervical spinal cord were counted on both sides after tissues were sectioned (50 microns) and processed for c-fos protein-like immunoreactivity (LI) using a rabbit polyclonal antiserum. C-fos protein-LI was visualized in the ventrolateral TNC, chiefly in laminae I and Ilo and predominantly within spinal segment C1-2 (e.g., -1.5 to -4.5 mm from obex) ipsilaterally. SD significantly increased cell staining within ipsilateral TNC. The ratio of cells in laminae I and Ilo on the left: right sides was 1.32 +/- 0.13 after 1 M KCl, as compared to 1.06 +/- 0.05 in control animals receiving 1 M NaCl instead of KCl microinjections (p < 0.01). The ratio was reduced to an insignificant difference after chronic surgical transection of meningeal afferents and recurrent SD (1.09 +/- 0.11). Pretreatment with intravenous sumatriptan, a 5-HT1-like receptor agonist that selectively blocks meningeal C-fibers and attenuates c-fos protein-LI within TNC after noxious meningeal stimulation, also reduced the ratio to an insignificant difference (1.10 +/- 0.09). Sumatriptan or chronic surgical transection of meningeal afferents, however, did not reduce the ability of KCl microinjections to induce SD. On the other hand, combined hyperoxia and hypercapnia not only reduced the number of evoked SDs from 6.3 +/- 1.0 to 2.5 +/- 1.2 after 0.15 M KCl microinjection, but also significantly (p < 0.01) reduced associated c-fos protein-LI in TNC. These data indicate that multiple neocortical SDs activate cells within TNC. The increase in c-fos protein-LI, observed predominantly ipsilaterally, was probably mediated by SD-induced stimulation of ipsilaterally projecting unmyelinated C-fibers innervating the meninges. If true, this is the first report demonstrating that neurophysiological events within cerebral cortex can activate brainstem regions involved in the processing of nociceptive information via trigeminovascular mechanisms.

Prostaglandin E2 and 4‐Aminopyridine Prevent the Lipopolysaccharide‐Induced Outwardly Rectifying Potassium Current and Interleukin‐1β Production in Cultured Rat Microglia

“…3) eicosanoids and anti-inflammatory drugs function in normal and pathologic brain tissue processes. Microglia are activated by diverse stimuli, including nerve transection (Graeber et al, 1988a,b;Morioka and Streit, 1991)) various neurological diseases (for review, see McGeer et al, 1993), and even a noninjurious stimulus, such as spreading depression (Gehrmann et al, 1993;, which may be associated with migraine headache (Moskowitz et al, 1993). In vitro stimuli, such as y-interferon (Wong et al, 1984) and LPS (Hetier et al, 1988), also activate microglia causing them to produce IL-l (Hetier et al, 1988) and tumor necrosis factor (Sawada et al, 1989)) alter expression of surface molecules (Imamura et al, 1991) , and enhance their NO production (Zielasek et al, 1992).…”

Role of cortical spreading depression in the pathophysiology of migraine

“…Cortical SD is thought to be a trigger of neurogenic inflammation around meningeal blood vessels, and then evokes headache pain via the activation of trigeminal afferents [11,12,56] . Bolay et al [13] demonstrated that cortical SD causes vasodilation of the middle meningeal artery and subsequent plasma protein leakage mediated by the release of pro-infl ammatory peptides from trigeminal axon collaterals innervating the meninges.…”

“…However, it is still controversial whether the neurogenic inflammation induced by cortical increase is abolished by trigeminal rhizotomy [56] . Moreover, cortical SD-evoked single neuron activity in the trigeminal ganglion (peripheral pathway) and the TNC has also been demonstrated directly by electrophysiological studies [17] .…”

Fisiopatologia da enxaqueca

“…Moskowitz e col. demonstraram que a passagem da depressão alastrante provoca a expressão de c-fos no núcleo do trigêmeo 41 . O pró-oncogene c-fos constitui um marcador não específico da ativação neuronal.…”