Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex

Abstract

The prostanoid-synthesizing enzyme cyclooxygenase-2 (COX-2) is expressed in selected cerebral cortical neurons and is involved in synaptic signaling. We sought to determine whether COX-2 participates in the increase in cerebral blood flow produced by synaptic activity in the somatosensory cortex. In anesthetized mice, the vibrissae were stimulated mechanically, and cerebral blood flow was recorded in the contralateral somatosensory cortex by a laser-Doppler probe. We found that the COX-2 inhibitor NS-398 attenuates the increase in somatosensory cortex blood flow produced by vibrissal stimulation. Furthermore, the flow response was impaired in mice lacking the COX-2 gene, whereas the associated increase in whisker-barrel cortex glucose use was not affected. The increases in cerebral blood flow produced by hypercapnia, acetylcholine, or bradykinin were not attenuated by NS-398, nor did they differ between wild-type and COX-2 null mice. The findings provide evidence for a previously unrecognized role of COX-2 in the mechanisms coupling synaptic activity to neocortical blood flow and provide an insight into one of the functions of constitutive COX-2 in the CNS.

Fig. 1.

Time course of the increase in CBF produced by vibrissal stimulation (Stim.) after topical application of NS-398 (A) and in COX-2 null mice (B). Vibrissal stimulation produces increases in CBF that reach a plateau after 10–20 sec of stimulation. The increase in CBF is attenuated by topical superfusion with NS-398 (100 μm) (A) or in COX-2 null mice (B) (p < 0.05; ttest).

Fig. 2.

Effect of the COX-2 inhibitor NS-398 on the increases in neocortical CBF produced by vibrissal stimulation (A) or hypercapnia (B). NS-398 was topically superfused on the exposed somatosensory cortex, and CBF was recorded by laser–Doppler flowmetry. NS-398 attenuates the increase in CBF produced by vibrissal stimulation (A) (p < 0.01; ANOVA and Tukey's test) but does not affect the response to hypercapnia (B) (p > 0.05).

Fig. 3.

Effect of NS-398 on the increase in CBF produced by topical application of the endothelial-dependent vasodilators acetylcholine (A) or bradykinin (B).

Fig. 4.

Effect of NS-398 on the increases in CBF produced by vibrissal stimulation (A) or hypercapnia (B) in homozygous COX-2 null mice (−/−) or in wild-type littermates (+/+). The response to whisker stimulation is attenuated in COX-2 null mice (p < 0.01). Furthermore, NS-398 (100 μm) attenuated the response in COX-2 +/+ but not in COX-2 −/− mice. The response to hypercapnia (B) is not affected in COX-2 −/− null mice and is not attenuated by NS-398 in either COX-2 −/− or +/+ mice (p > 0.05).

Fig. 5.

Effect of NS-398 on the increases in CBF produced by acetylcholine (A) or bradykinin (B) in homozygous COX-2 null mice (−/−) or in wild-type littermates. These responses are not affected in COX-2 −/− null mice and are not attenuated by NS-398 (100 μm) in either COX-2 −/− or +/+ mice (p > 0.05).

Fig. 6.

Effect of vibrissal stimulation on CGU in the somatosensory cortex of COX-2 null mice. Vibrissal stimulation produces comparable increases in CGU in COX-2 wild-type (+/+) and null (−/−) mice. See Table 2 for group values.