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Alterations in Neurokinin A-, Substance P- and Calcitonin Gene- Related

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Alterations in Neurokinin A-, Substance P- and Calcitonin Gene- Related Neuroscience Letters 261 (1999) 179–182 Alterations in neurokinin A-, substance P- and calcitonin gene- related peptide immunoreactivities in the caudal trigeminal nucleus of the rat following electrical stimulation of the trigeminal ganglion M. Samsama,b, R. Coven˜asa,*, R. Ahangaria,b, J. Yajeyaa,c, J.A. Narva´ezd, G. Tramue aInstituto de Neurociencias de Castilla y Leo´n, Laboratorio de Neuroanatomı´a de los Sistemas Peptide´rgicos, Facultad de Medicina, Dpto. de Biologı´a Celular y Patologı´a, C/Alfonso X El Sabio, s/n 37007 Salamanca, Spain bDepartamento de Biologı´a Celular y Patologı´a, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain cDepartamento de Fisiologı´a y Farmacologı´a, Facultad de Medicina, Universidad de Salamanca, Salamanca, Spain dDepartamento de Fisiologı´a, Facultad de Medicina, Universidad de Ma´laga, Ma´laga, Spain eUniversite´ de Bordeaux I, Laboratoire de Neurocytochimie Fonctionnelle, CNRS, URA 339, Talence, France Received 30 November 1998; received in revised form 6 January 1999; accepted 6 January 1999 Abstract We have carried out an immunohistochemical study on the presence of neurokinin A (NKA) and substance P (SP) in the rat caudal trigeminal nucleus (CTN) after electrical stimulation of the trigeminal ganglion (TG), used as an experimental model to induce alterations, some of which may occur during migraine attacks (release of vasoactive peptides from perivascular trigeminal axons and neurogenic inflammation). Both unilateral, 30 min electrical stimulation (5 Hz, 5 ms, 0.1–1 mA) of the TG and 5 min stimulation with a slight increase in the stimulating parameters (7.5 Hz, 5 ms, 1.4 mA) caused a significant depletion of the NKA and SP immunoreactivities (-IR) of the TG nerve central terminals in the ipsilateral CTN. Calcitonin gene-related peptide (CGRP)-IR of the ipsilateral CTN was also studied in the CTN using the increased stimulating parameters and a marked depletion of CGRP-IR was also observed following TG stimulation. Such depletion may be due to the release of neuropeptides from the trigeminal central terminals. These findings suggest that NKA, SP and CGRP could act as neurotransmitters at the first central synapses of the trigeminal nociceptive pathway to transmit the sensory stimuli to the higher brain centers. 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Neurokinin A; Substance P; Calcitonin gene-related peptide; Migraine; Trigeminal ganglion; Electrical stimulation; Caudal trigeminal nucleus It is known that the central terminals of the rat trigeminal with neurokinin A (NKA) [4] exist in TG cells and their ganglion (TG) sensory neurons reach the brain stem, mainly fibers. It has also been proved that neuropeptides are the trigeminal sensory nuclei [16], and that the peripheral involved in the pathogenesis of migraine headaches axons of some trigeminal ganglion neurons are responsible [13,19]. In this respect, neurogenic inflammation in the for the main innervation of the dura mater [15]. Moreover, dural blood vessels has been suggested as a model to there is evidence that neuropeptides such as substance P mimic vascular head pain [13]. In keeping with this, elec- (SP) and calcitonin gene-related peptide (CGRP) together trical stimulation of the TG promotes the extravasation of albumin from plasma in the postcapillary venules of the dura mater, possibly through the release of neuropeptides * Corresponding author. Tel.: +34-923-294400 ext. 1856; fax: +34- [12]. Moreover, electrical stimulation of the TG increases 923-294549; e-mail: [email protected] CGRP levels in the rat superior sagittal sinus [2]. This is in 0304-3940/99/$ - see front matter 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(98)00989-6 180 M. Samsam et al. / Neuroscience Letters 261 (1999) 179–182 agreement with the increased levels of CGRP in blood this work showed immunohistochemical cross-reactivities obtained from the jugular vein of human subjects during with neurokinin B, eledoisin, and kassinin. Finally, possible migraine [6]. Consistent with this, thermocoagulation of interference by endogenous peroxidases was ruled out by the TG in human and also electrical stimulation of the TG staining some sections beginning with the diaminobenzi- in cat increased SP and CGRP levels in plasma [5]. Appar- dine step. Immunohistochemical assays were carried out ently electrical stimulation of the TG induces a series of as described previously, the tissue-bound peroxidase was cellular and chemical changes consistent with some findings revealed by using the 3,3′ diaminobenzidine method [11]. observed during migraine attacks. In view of this, we were The central terminals of primary sensory TG cells exhibit prompted to investigate NKA-, SP- and CGRP-IRs of the a strong NKA-, SP- and CGRP-IR and form a curved lami- central trigeminal terminals in the rat caudal trigeminal nar pattern in the rat CTN on both sides close to the dorsal nucleus (CTN) following electrical stimulation of the TG surface of the medulla, as observed by light microscopic to get further insight into the role and action of these neu- examination under normal condition. No differences in the ropeptides in nociception. immunoreactivity of either side were observed in the control Twenty seven young adult Wistar albino rats of both animals. Five minutes electrical stimulation of the TG in sexes (weight 200–250 g) were used in this study. The group 1 animals (reference parameter), did not cause any animals were deeply anesthetized with chloral hydrate apparent change in the NKA- or SP-IR of the CTN of both (4%) and were placed in a stereotactic apparatus. One side sides, but 30 min stimulation of the TG in the second group TG of the animals were electrically stimulated with square induced a marked decrease in neuropeptide-IR in the ipsi- pulses using a concentric bipolar electrode (0.5 mm in dia- lateral (stimulated side) CTN (Fig. 1A,B). Stimulation of meter). The stimulation coordinates used to reach the gang- lion were according to Schneider et al. [18]: bregma = zero point, 3.2–3.4 mm posteriorly and 2.8–3.2 mm lateral to the bregma and 9.3 mm depth from the external surface of the dura. The animals were divided into four groups (six ani- mals/groups I, II or IV, and nine animals/group III). Group 1, stimulated according to the following parameters: 5 Hertz (Hz) frequency, 5 ms duration and 0.1–1 milliamps (mA) amplitude (reference parameter) for 5 min. Group 2: stimu- lated with the same parameters for 30 min. Group 3: stimu- lated with 7.5 Hz, 5 ms, and 1.4 mA (new parameter) for 5 min. Group 4: used as control animals without any stimula- tion. Every two rats from groups I, II or IV were investi- gated for only one neuropeptide (SP or NKA or CGRP) and in group III, every three rats were investigated for either neuropeptide. Immediately following stimulation, the ani- mals were subjected to transcardial flushing with 100 ml cold physiologic saline (NaCl 0.9%) followed by 500 ml cold fixative solution (4% paraformaldehyde), then, medulla was removed and postfixed overnight. Fifty-milli- meter thick frozen sections from medulla (between Obex and the cervical segment 1) were obtained using a cryostat. Sections were treated with a mixture of methanol and H2O2 for 30 min and then transferred into the SP or NKA or Fig. 1. Neuropeptide immunoreactivity (-IR) in the caudal trigeminal nucleus (CTN) of the rat after a unilateral electrical stimulation of the CGRP primary antibody (1/1500, 1/2500, 1/1500 dilution trigeminal ganglion (TG). (A,B) are parts of the same section of the respectively) for 16 h. Polyclonal primary antibodies were medulla; (A) Substance P (SP)-IR in the CTN (arrows) in the normal raised in rabbits against their respective immunogens. These or non-stimulated side (NS). (B) Depletion of the SP-IR (arrows) in were prepared by coupling the antigens (the whole synthetic the CTN of the stimulated (S) side following a unilateral 30 min peptides, SP, CGRP or NKA) to a carrier protein (human electrical stimulation (reference parameters) of the TG. (C,D) are two sides of the same section of the medulla; (C) SP-IR in the serum albumin) with glutaraldehyde. Immunostaining was CTN (arrows) in the non-stimulated (NS) side and (D) shows a sig- controlled by treating each of the three antisera with an nificant depletion of the SP-IR in the CTN of the stimulated (S) side excess (100 mg/ml of diluted antiserum at 1/1500, 1/ after 5 min unilateral stimulation of the TG with the new parameters. 2500) of the homologous antigen, and by omitting the first The arrow in (D) is pointing to a few immunoreactive nerve terminals. antisera in the first incubation bath. In both cases no residual (E,F) Are also parts of the same section of the medulla; using the new parameters, a unilateral 5 min electrical stimulation of the TG immunoreactivity was found. Preabsorption with heterolo- caused a marked disappearance of the CGRP-IR in the CTN gous antigens (e.g. SP or CGRP to antineurokinin A serum) (arrows) of the stimulated (S) side (E) comparing to the non-stimu- did not block specific staining. None of the antisera used in lated (NS) side of the same section (F). Scale bar, 100 mm. M. Samsam et al. / Neuroscience Letters 261 (1999) 179–182 181 Fig. 2. (A) NKA-IR in the CTN of the rat after a 5 min unilateral electrical stimulation of the TG; a marked depletion of the NKA-IR can be observed in the stimulated (S) side comparing to the normal or non-stimulated (NS) side. (B) and (C) are the higher magnification of the CTN in (A) which have been indicated in squares; (B) a few immunoreactive nerve terminals (arrow heads) can be seen in the stimulated (S) side comparing to the non-stimulated (NS) side (C).
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