TY - JOUR
T1 - Attenuation by valproate of c‐fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin
AU - Cutrer, F. Michael
AU - Limmroth, Volker
AU - Ayata, Gamze
AU - Moskowitz, Michael A.
PY - 1995/12
Y1 - 1995/12
N2 - Valproic acid, useful in the treatment of migraine, is an inhibitor of γ‐aminobutyric acid (GABA) aminotransferase and activator of glutamic add decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2‐propylpentanoic acid) were examined on the number of cells expressing c‐fos‐like immunoreactivity (c‐fos‐LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, II0; TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 μ ml−1, in urethane‐anaesthetized Hartley guinea‐pigs. Positive cells were counted in eighteen sections (50 μm) at three representative levels (rostral, middle and caudal) within lamina I, II0 of the TNC in 90 animals. Numerous cells were labelled after capsaicin instillation (244 ± 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 ± 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. Valproate (≥ 10 mg kg−1, i.p.) reduced labelled cells by 52% (P<0.05) in lamina I, II0 but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. Pretreatment with bicuculline (30 μg kg−1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg−1) a GABAB antagonist, reversed the effect of valproate and increased c‐fos positive cells within lamina I, II0. Somewhat paradoxically, bicuculline by itself (30 μg kg−1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c‐fos expression. We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c‐fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches. 1995 British Pharmacological Society
AB - Valproic acid, useful in the treatment of migraine, is an inhibitor of γ‐aminobutyric acid (GABA) aminotransferase and activator of glutamic add decarboxylase. Its mechanism in migraine remains obscure. The effects of valproic acid (2‐propylpentanoic acid) were examined on the number of cells expressing c‐fos‐like immunoreactivity (c‐fos‐LI), a marker of neuronal activation, within the trigeminal nucleus caudalis (lamina I, II0; TNC) 2 h after intracisternal injection of the irritant, capsaicin (0.1 ml; 15.25 μ ml−1, in urethane‐anaesthetized Hartley guinea‐pigs. Positive cells were counted in eighteen sections (50 μm) at three representative levels (rostral, middle and caudal) within lamina I, II0 of the TNC in 90 animals. Numerous cells were labelled after capsaicin instillation (244 ± 25; 1 ml; 15.25 mM) but not after capsaicin vehicle (11 ± 1). Positive cells were also found within the medial reticular nucleus, the area postrema and the nucleus of the solitary tract. A similar distribution has been demonstrated previously after application of intracisternal irritants such as autologous blood or carrageenin. Valproate (≥ 10 mg kg−1, i.p.) reduced labelled cells by 52% (P<0.05) in lamina I, II0 but not within the area postrema, the nucleus of the solitary tract or the medial reticular nucleus. A similar finding was obtained previously after administration of sumatriptan, dihydroergotamine or the NK1 receptor antagonist RPR 100,893. Pretreatment with bicuculline (30 μg kg−1; i.p.), a GABAA antagonist, but not phaclofen (1 mg kg−1) a GABAB antagonist, reversed the effect of valproate and increased c‐fos positive cells within lamina I, II0. Somewhat paradoxically, bicuculline by itself (30 μg kg−1 i.p.) decreased the number of labelled cells suggesting that more than a single GABAergic mechanism can suppress c‐fos expression. We conclude that the mechanism of action of valproate is mediated via GABAA receptors. Since valproate decreases both c‐fos expression and as previously shown, neurogenic inflammation within the meninges, the GABAA receptor complex might provide an important target for drug development in migraine and related headaches. 1995 British Pharmacological Society
KW - GABA
KW - bicuculline
KW - c‐fos
KW - headache
KW - migraine
KW - trigeminal
KW - valproate
UR - http://www.scopus.com/inward/record.url?scp=0029617710&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029617710&partnerID=8YFLogxK
U2 - 10.1111/j.1476-5381.1995.tb15124.x
DO - 10.1111/j.1476-5381.1995.tb15124.x
M3 - Article
C2 - 8719796
AN - SCOPUS:0029617710
SN - 0007-1188
VL - 116
SP - 3199
EP - 3204
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 8
ER -