Capsaicin-insensitive sensory-efferent meningeal vasodilatation evoked by electrical stimulation of trigeminal nerve fibres in the rat

Abstract

1. Antidromic vasodilatation and plasma extravasation to stimulation of the trigeminal ganglion or its perivascular meningeal fibres was investigated by laser-Doppler flowmetry and 125I-labelled bovin serum albumin in the dura mater and in exteroceptive areas (nasal mucosa, upper eyelid) of anaesthetized rats pretreated with guanethidine and pipecuronium. 2 Trigeminal stimulation at 5 Hz for 20 s elicited unilateral phasic vasodilatation in the dura and lasting response in the nasal mucosa. Resiniferatoxin (1-3 microg kg(-1) i.v.), topical (1%) or systemic capsaicin pretreatment (300 mg kg(-1) s.c. plus 1 mg kg(-1) i.v.) did not inhibit the meningeal responses but abolished or strongly inhibited the nasal responses. Administration of vinpocetine (3 mg kg(-1) i.v.) increased both basal blood flow and the dural vasodilatation to perivascular nerve stimulation. 3. Dural vasodilatation to trigeminal stimulation was not inhibited by the calcitonin gene-related peptide-1 receptor (CGRP-1) antagonist hCGRP8-37 (15 or 50 microg kg(-1) i.v), or the neurokinin-1 receptor antagonist RP 67580 (0.1 mg kg(-1) i.v.) although both antagonists inhibited the nasal response. Neither mucosal nor meningeal responses were inhibited by atropine (5 mg kg(-1) i.v.), hexamethonium (10 mg kg(-1) i.v.) or the vasoactive intestinal polypeptide (VIP) antagonist (p-chloro-D-Phe6-Leul7)VIP (20 microg kg(-1) i.v.). 4. Plasma extravasation in the dura and upper eyelid elicited by electrical stimulation of the trigeminal ganglion was almost completely abolished in rats pretreated with resiniferatoxin (3 microg kg(-1) i.v.). 5. It is concluded that in the rat meningeal vasodilatation evoked by stimulation of trigeminal fibres is mediated by capsaicin-insensitive primary afferents, while plasma extravasation in the dura and upper eyelid and the vasodilatation in the nasal mucosa are mediated by capsaicin-sensitive trigeminal fibres.

Figure 1

Meningeal blood flow enhancements evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the dura mater before and after resiniferatoxin (RTX, 3 μg kg⁻¹ i.v.) application (A). Meningeal and nasal blood flow enhancements evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion (B). Blood flow records of the ipsilateral and contralateral sides of the dura mater during electrical stimulation of the left trigeminal ganglion (C). BP: blood pressure, AU: arbitrary unit, MBF: meningeal blood flow, NBF: nasal blood flow, arrowheads: electrical stimulations, arrow: resiniferatoxin injection.

Figure 2

Left: Effect of vinpocetine infusion (3 mg kg⁻¹ i.v. at a rate of 0.1 mg kg⁻¹ min⁻¹ for 30 min) on meningeal blood flow responses evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the dura mater. The terminal part of a similar infusion of the solvent is also shown. Right: Per cent increase in blood flow values at the end of vinpocetine infusion [area under the curve (AUC); n=6; mean±s.e.mean ^*P<0.05]. BP: blood pressure, AU: arbitrary unit, MBF: meningeal blood flow, arrowheads: electrical stimulations.

Figure 3

Frequency-response curves of meningeal and nasal blood flow enhancements (means±s.e.mean) evoked by electrical stimulation (15 V, 0.5 ms, 100 impulses) of the ipsilateral trigeminal ganglion (n=6; max: response maximum; AUC: area under the curve).

Figure 4

Effect of guanethidine (8 mg kg⁻¹ i.v.) and capsaicin (cumulative dose of 1 mg kg⁻¹ i.v.) on blood pressure and on meningeal and nasal blood flow enhancements evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion in a capsaicin pretreated (total dose: 300 mg kg⁻¹) rat. BP: blood pressure, AU: arbitrary unit, MBF: meningeal blood flow, NBF: nasal blood flow, arrowheads: electrical stimulations, arrows: injection of drugs.

Figure 5

Quantitative evaluation of the effect of resiniferatoxin (RTX, 3 μg kg⁻¹ i.v.; n=15), local (1%; n=6) or systemic application of capsaicin (cumulative dose of 1 mg kg⁻¹ i.v. in capsaicin pretreated rats with a total dose of 300 mg kg⁻¹; n=6) on dural and nasal blood flow enhancement evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion. Responses are expressed as percentage deviation from control values (means±s.e.m). ^*P<0.05, ^**P<0.01. N.S., non significant.

Figure 6

Effect of hCGRP_8–37 (15+35 μg kg⁻¹ i.v.) on blood flow enhancement in the dura and nasal mucosa evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion. BP: blood pressure, AU: arbitrary unit, MBF: meningeal blood flow, NBF: nasal blood flow, arrowheads: electrical stimulations, arrows: injection of drug.

Figure 7

(A) Quantitative evaluation of the effect of hCGRP_8–37 (15 μg kg⁻¹ i.v.; n=6), atropine (5 mg kg⁻¹ i.v.; n=6), hexamethonium (10 mg kg⁻¹ i.v.; n=6), p-chloro-D-Phe⁶-Leu1⁷-VIP (20 μg kg⁻¹ i.v.; n=6) and RP 67580 (0.1 mg kg⁻¹ i.v.; n=18) on the blood flow increase in the dura mater evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion. (B) Quantitative evaluation of the effect of hCGRP_8–37 (15 μg kg⁻¹ i.v.; n=6), atropine (5 mg kg⁻¹ i.v.; n=6), p-chloro-D-Phe⁶-Leu1⁷-VIP (20 μg kg⁻¹ i.v.; n=6) and RP 67580 (0.1 mg kg⁻¹ i.v. n=12) on the blood flow increase in the nasal mucosa evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion. Responses are expressed as percentage deviation from control values (means±s.e.mean). ^*P<0.05, N.S., non significant.

Figure 7

(A) Quantitative evaluation of the effect of hCGRP_8–37 (15 μg kg⁻¹ i.v.; n=6), atropine (5 mg kg⁻¹ i.v.; n=6), hexamethonium (10 mg kg⁻¹ i.v.; n=6), p-chloro-D-Phe⁶-Leu1⁷-VIP (20 μg kg⁻¹ i.v.; n=6) and RP 67580 (0.1 mg kg⁻¹ i.v.; n=18) on the blood flow increase in the dura mater evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion. (B) Quantitative evaluation of the effect of hCGRP_8–37 (15 μg kg⁻¹ i.v.; n=6), atropine (5 mg kg⁻¹ i.v.; n=6), p-chloro-D-Phe⁶-Leu1⁷-VIP (20 μg kg⁻¹ i.v.; n=6) and RP 67580 (0.1 mg kg⁻¹ i.v. n=12) on the blood flow increase in the nasal mucosa evoked by electrical stimulation (15 V, 5 Hz, 0.5 ms, 20 s) of the ipsilateral trigeminal ganglion. Responses are expressed as percentage deviation from control values (means±s.e.mean). ^*P<0.05, N.S., non significant.

Figure 8

Effect of resiniferatoxin (RTX, 3 μg kg⁻¹ i.v. 10 min. before electrical stimulation; n=6) on plasma extravasation in the dura mater and in the upper eyelid evoked by electrical stimulation (25 V, 5 Hz, 0.5 ms, 5 min) of the ipsilateral trigeminal ganglion (means±s.e.mean; c.p.m.: count per minute; ^*P<0.01; N.S., non significant).