Increase of capsaicin-induced trigeminal Fos-like immunoreactivity by 5-HT(7) receptors

Abstract

Objective: To explore whether pharmacological stimulation of the 5-hydroxytryptamine(7) (5-HT(7) ) receptor modulates Fos-like immunoreactivity in the trigeminal nucleus caudalis of rats.

Background: The serotonin 5-HT(7) receptor was proposed to be involved in migraine pathogenesis and evidence suggests it plays a role in peripheral nociception and hyperalgesia through an action on sensory afferent neurons.

Methods: The potential activating or sensitizing role of 5-HT(7) receptors on trigeminal sensory neurons, as visualized by Fos-like immunoreactivity in the superficial layers of the trigeminal nucleus caudalis in rats, was investigated using the 5-HT(7) receptor agonist, LP-211, in the absence and the presence of intracisternal capsaicin, respectively. The agonist effect was characterized with the 5-HT(7) receptor antagonist, SB-656104. Male Wistar rats received a subcutaneous injection of LP-211, SB-656104, and SB-656104 + LP-211. They were then anesthetized and prepared to receive an intracisternal injection of capsaicin or its vehicle. Animals were perfused and brains removed; sections of the brain stem from the area postrema to the CI level were obtained and processed for Fos immunohistochemistry.

Results: Capsaicin but not its vehicle induced Fos-like immunoreactivity within laminae I and II of trigeminal nucleus caudalis. Pretreatment with LP-211 had no effect on Fos-like immunoreactivity but strongly increased the response produced by capsaicin; this effect was abolished by SB-656104. Interestingly, capsaicin-induced Fos-like immunoreactivity was abolished by SB-656104 pretreatment thus suggesting involvement of endogenous 5-HT.

Conclusions: Data suggest that 5-HT(7) receptors increase activation of meningeal trigeminovascular afferents and/or transmission of nociceptive information in the brain stem. This mechanism could be relevant in migraine and its prophylactic treatment.

Figure 1

Distribution of Fos-immunoreactive cells in Sp5C (LI-II). Treatments were as follows: vehicle (i.c.) (A,B); capsaicin (1 μM, i.c.) (C,D); LP-211 (10 mg/kg, s.c.) + capsaicin (1 μM, i.c.) (E,F); and SB656104A (3 mg/kg, s.c.) + LP-211 (10 mg/kg, s.c.) + capsaicin (1 μM, i.c.) (G,H). Upper and lower panels show, respectively, 10× and 20× microphotographs of the same preparation. Inserts in upper panels demarcate the areas shown in the lower panel microphotographs. Bars = 200 μm (upper panels) and 100 μm (lower panels).

Figure 2

The Fos response in the trigeminal nucleus caudalis after intracisternal (i.c.) or subcutaneous (s.c.) administration of vehicle for capsaicin (VEH; i.c.), capsaicin (CAP; 1 μM, i.c.), LP-211 (LP; 10 mg/kg, s.c.) and SB-656104A (SB; 3 mg/kg, s.c.) combined as indicated. CAP caused a robust induction of Fos-like immunoreactivity within laminas I and II as detected 2 h after injection. Each bar represents the mean number of Fos-immunopositive cells per 40-μm section and vertical lines denote the standard error of the mean of 6-7 observations. * P < 0.01 vs VEH; ** P < 0.001 vs CAP or LP + VEH; + P < 0.01 vs CAP; # P < 0.001 vs LP + CAP