Non-NMDA glutamate receptors modulate capsaicin induced c-fos expression within trigeminal nucleus caudalis

Abstract

1. We examined the effects of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzol[f]quinoxaline-7-sulpho namide (NBQX), the kainate receptor antagonists gamma-(R-)-glutamylaminomethanesulphonic acid (GAMS) and 6,7,8,9-tetrahydro-5-nitro-1H-benz[g]indole-2,3-dione-3-oxime (NS-102), and the group III metabotropic glutamate receptor (mGluR) agonist 2-amino-4-phosphono-S-butanoic acid (L-AP4) on c-fos-like immunoreactivity (c-fos LI) in trigeminal caudalis (Sp5C), lateral reticular (LRt), medullary reticular (Md) and solitary tract (Sol) nuclei, after intracisternal injection of capsaicin in urethane anaesthetized Sprague-Dawley rats. 2. Few c-fos labelled cells were observed within Sp5C in capsaicin-vehicle treated animals. The number of positive c-fos cells increased by 17 fold after intracisternal capsaicin (5 nmol) administration. 3. Pretreatment with CNQX (0.02, 0.1, 0.6, 3 and 15 mg kg-1) or NBQX (0.01, 0.1 and 1 mg kg-1), administered intraperitoneally 15 min before capsaicin, significantly reduced labelled cells within Sp5C by a maximum of 45 and 34%, respectively. The number of c-fox LI cells within LRt, Md and Sol was not affected. Pretreatment with L-AP4 (1, 3 and 10 mg kg-1) decreased the number of Sp5C c-fos LI cells by a maximum of 30%, whereas GAMS (1 and 10 mg kg-1) and NS-102 (1 and 5 mg kg-1) did not show any significant effect. 4. These results suggest that blockade of AMPA receptors, but not kainate receptors, or the activation of group III mGluRs, decrease the response of Sp5C neurons to trigeminovascular activation. Thus, in addition to NMDA receptors, mGluRs and AMPA receptors may modulate cephalic pain and may provide a potential therapeutic target for antimigraine drugs.

Figure 1

Camera lucida drawings showing the location of c-fos antigen immunostained cells (dots) within superficial laminae of trigeminal nucleus caudalis (Sp5C) and the deeper laminae of solitary tract nucleus (Sol), lateral reticular nucleus (LRt) and medullary reticular nucleus (Md), in coronal brain stem sections taken from two representative animals treated with intracisternal capsaicin (5 nmol). C-fos expression was detected bilaterally and most intensely within dorsal than ventral aspects of laminae I and II, being greatest at −2.05 mm (2a), as previously has been reported (a images, drug-vehicle treated animal). Pretreatment with CNQX (15 mg kg⁻¹; b images) reduced the c-fos positive cells per 50 μm section at each level of Sp5C, from dorsal (obex, 1b) to caudal (obex−6.45 mm, 3b), but not in Sol, LRt and Md. These nuclei are also labelled in capsaicin-vehicle treated animals, or intact anaesthetized animals, suggesting that intraperitoneal injection, or urethane, or both, could be the primary trigger. Sections 1, obex; sections 2, −2.05 mm; and sections 3, spinal cord (−6.25 mm). All the drawings have the same magnification.

Figure 2

Pretreatment with CNQX and NBQX dose-dependently decreased capsaicin-induced c-fos immunoreactivity (c-fos LI) within trigeminal nucleus caudalis (laminae I, II). Drugs were given intraperitoneally followed by intracisternal injection of capsaicin (5 nmol). Animals were euthanized 2 h after menigeal irritation with capsaicin. Data are presented as percentage of decrease of c-fos LI cells per section (weighted average, see methods).